Antibacterial compounds and uses thereof

ABSTRACT

The present invention relates to compounds of formula (I) including any stereochemically isomeric form thereof, or pharmaceutically acceptable salts thereof, for the treatment of tuberculosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application of PCT/US2017/021031filed Mar. 7, 2017, which claims priority from U.S. Provisional PatentApplication No. 62/304,661, filed on Mar. 7, 2016. The priority of bothsaid PCT and U.S. Provisional Patent Application are claimed. Each ofprior mentioned applications is hereby incorporated by reference hereinin its entirety.

FIELD OF THE INVENTION

The invention relates generally to diarylquinoline compounds withantibacterial activity and, more specifically, with anti-tuberculosisproperties. All documents cited to or relied upon below are expresslyincorporated herein by reference.

BACKGROUND OF THE INVENTION

Mycobacterium tuberculosis is the causative agent of tuberculosis(“TB”), a devastating infectious disease. It is estimated that about 2million TB patients die each year globally. Failure to properly treattuberculosis has caused global drug resistance in mycobacteriumtuberculosis, thus rendering some medications ineffective.

A need exists in the art for pharmaceutical compounds that provideadvantages over compounds currently used in the art.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I):

including any stereochemically isomeric form thereof,wherein:

-   R₁ is phenyl, optionally mono- or bi-substituted independently with    lower alkyl, halogen or alkoxy,    -   5- or 6-membered heteroaryl, optionally mono-, bi- or        tri-substituted independently with lower alkyl, halogen, alkoxy,        —SCH₃, SCH₂CH₃, —N(CH₂CH₃)₂ or —N(CH₃)₂,    -   benzofuranyl,    -   2,3-dihydrobenzo[b][1,4]dioxin-5-yl,    -   2,3-dihydro-1H-inden-4-yl or    -   5,6,7,8-tetrahydro naphthalene-1-yl;-   R₂ and R₃, independently of each other, are hydrogen or lower alkyl;-   R₄ is -phenyl, optionally mono- or bi-substituted independently with    halogen or lower alkyl,    -   5- or 6-membered heteroaryl, optionally mono-, bi- or        tri-substituted independently with alkoxy, —O-cycloalkyl,        —S-loweralkyl, difluoromethoxy or —N(CH₃)₂,    -   benzofuranyl,    -   benzo[b]thiophenyl or    -   2,3-dihydro-1H-indenyl; and-   R₅ is halogen or cyano,-   or a pharmaceutically acceptable salt thereof.

The present invention is also directed to a pharmaceutical composition,comprising a therapeutically effective amount of a compound according toformula I, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

The present invention is further directed to a method for the treatmentof tuberculosis, comprising the step of administering to a patient inneed thereof a therapeutically effective amount of a compound accordingto formula I, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the descriptions of the present inventionhave been simplified to illustrate elements that are relevant for aclear understanding of the present invention, while eliminating, for thepurpose of clarity, many other elements found in typical pharmaceuticalcompositions. Those of ordinary skill in the art will recognize thatother elements and/or steps are desirable and/or required inimplementing the present invention. However, because such elements andsteps are well known in the art, and because they do not facilitate abetter understanding of the present invention, a discussion of suchelements and steps is not provided herein. The disclosure herein isdirected to all such variations and modifications to such elements andmethods known to those skilled in the art. Furthermore, the embodimentsidentified and illustrated herein are for exemplary purposes only, andare not meant to be exclusive or limited in their description of thepresent invention.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference are made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

A compound according to the invention is inherently intended to compriseall stereochemically isomeric forms thereof. The term “stereochemicallyisomeric forms” as used hereinbefore or hereinafter defines all thepossible stereoisomeric forms which the compounds of formula (I), andtheir N-oxides, pharmaceutically acceptable salts or physiologicallyfunctional derivatives may possess. Unless otherwise mentioned orindicated, the chemical designation of compounds denotes the mixture ofall possible stereochemically isomeric forms. In particular, stereogeniccenters may have the R- or S-configuration; substituents on bivalentcyclic (partially) saturated radicals may have either the cis- ortrans-configuration. Compounds encompassing double bonds can have an E(entgegen) or Z (zusammen)-stereochemistry at said double bond. Theterms cis, trans, R, S, E and Z are well known to a person skilled inthe art.

Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention. Ofspecial interest are those compounds of formula (I) which arestereochemically pure.

Following CAS-nomenclature conventions, when two stereogenic centers ofknown absolute configuration are present in a molecule, an R or Sdescriptor is assigned (based on Cahn-Ingold-Prelog sequence rule) tothe lowest-numbered chiral center, the reference center. Theconfiguration of the second stereogenic center is indicated usingrelative descriptors [R*,R*] or [R*,S*], where R* is always specified asthe reference center and [R*,R*] indicates centers with the samechirality and [R*,S*] indicates centers of unlike chirality. Forexample, if the lowest-numbered chiral center in the molecule has an Sconfiguration and the second center is R, the stereo descriptor would bespecified as S—[R*,S*]. If “α” and “β” are used: the position of thehighest priority substituent on the asymmetric carbon atom in the ringsystem having the lowest ring number, is arbitrarily always in the “α”position of the mean plane determined by the ring system. The positionof the highest priority substituent on the other asymmetric carbon atomin the ring system relative to the position of the highest prioritysubstituent on the reference atom is denominated “α”, if it is on thesame side of the mean plane determined by the ring system, or “β”, if itis on the other side of the mean plane determined by the ring system.

When a specific stereoisomeric form is indicated, this means that saidform is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, further preferably less than 2% and mostpreferably less than 1% of the other isomer(s). Thus, when a compound offormula (I) is for instance specified as (R,S), this means that thecompound is substantially free of the (S,R) isomer.

Compounds of formula (I) and some of the intermediate compoundsinvariably have at least two stereogenic centers in their structurewhich may lead to at least 4 stereochemically different structures.

The compounds of formula (I) may be synthesized in the form of mixtures,in particular racemic mixtures, of enantiomers which can be separatedfrom one another following art-known resolution procedures. The racemiccompounds of formula (I) may be converted into the correspondingdiastereomeric salt forms by reaction with a suitable chiral acid. Saiddiastereomeric salt forms are subsequently separated, for example, byselective or fractional crystallization and the enantiomers areliberated therefrom by alkali. An alternative manner of separating theenantiomeric forms of the compounds of formula (I) involves liquidchromatography using a chiral stationary phase. Said purestereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound will be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The tautomeric forms of the compounds of formula (I) are meant tocomprise those compounds of formula (I) wherein e.g. an enol group isconverted into a keto group (keto-enol tautomerism). Tautomeric forms ofthe compounds of formula (I) or of intermediates of the presentinvention are intended to be embraced by the ambit of this invention.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl,” or “hydroxyalkyl,” this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” denotes the radical R′R″—, wherein R′ is a phenyl radical,and R″ is an alkylene radical as defined herein with the understandingthat the attachment point of the phenylalkyl moiety will be on thealkylene radical. Examples of arylalkyl radicals include, but are notlimited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl”or “aralkyl” are interpreted similarly except R′ is an aryl radical. Theterms “(het)arylalkyl” or “(het)aralkyl” are interpreted similarlyexcept R′ is optionally an aryl or a heteroaryl radical.

The terms “haloalkyl” or “halo lower alkyl” or “lower haloalkyl” refersto a straight or branched chain hydrocarbon residue containing 1 to 6carbon atoms wherein one or more carbon atoms are substituted with oneor more halogen atoms.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an —O-alkyl wherein alkyl is C₁₋₁₀.

The terms “haloalkoxy” or “halo lower alkoxy” or “lower haloalkoxy”refers to a lower alkoxy group, wherein one or more carbon atoms aresubstituted with one or more halogen atoms.

The term “hydroxyalkyl” as used herein denotes an alkyl radical asherein defined wherein one to three hydrogen atoms on different carbonatoms is/are replaced by hydroxyl groups.

The term “sulfonyl” as used herein denotes a —SO₂— group.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refers to agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” asused herein refers herein denotes a group of formula —S(═O)₂R wherein Ris “heteroalkyl” as defined herein.

The term “lower alkyl sulfonylamido” as used herein refers to a group offormula —S(═O)₂NR₂ wherein each R is independently hydrogen or C₁₋₃alkyl, and lower alkyl is as defined herein.

The term “carboxyl” as used herein refers to a group of formula —C(═O)R₂wherein each R is independently hydrogen or C₁₋₃ alkyl, and lower alkylis as defined herein.

The term “cycloalkyl” denotes a monovalent saturated monocyclic orbicyclic hydrocarbon group of 3 to 10 ring carbon atoms. In particularembodiments cycloalkyl denotes a monovalent saturated monocyclichydrocarbon group of 3 to 8 ring carbon atoms. Bicyclic means consistingof two saturated carbocycles having one or more carbon atoms in common.Particular cycloalkyl groups are monocyclic. Examples for monocycliccycloalkyl are cyclopropyl, cyclobutanyl, cyclopentyl, cyclohexyl orcycloheptyl. Examples for bicyclic cycloalkyl arebicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl.

The term “amino” as used herein denotes a group of the formula —NR′R″wherein R′ and R″ are independently hydrogen, alkyl, alkoxy, cycloalkyl,heterocycloalkyl, aryl or heteroaryl. Alternatively, R′ and R″, togetherwith the nitrogen to which they are attached, can form aheterocycloalkyl. The term “primary amino” denotes a group wherein bothR′ and R″ are hydrogen. The term “secondary amino” denotes a groupwherein R′ is hydrogen and R″ is not. The term “tertiary amino” denotesa group wherein both R′ and R″ are not hydrogen. Particular secondaryand tertiary amines are methylamine, ethylamine, propylamine,isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine,dipropylamine and diisopropylamine.

The term “heteroaryl” denotes a monovalent aromatic heterocyclic mono-or bicyclic ring system of 5 to 12 ring atoms, comprising 1, 2, 3 or 4heteroatoms selected from N, O and S, the remaining ring atoms beingcarbon. Examples of heteroaryl moieties include pyrrolyl, furanyl,thienyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrazolyl, pyridazinyl,pyrimidinyl, triazinyl, azepinyl, diazepinyl, isoxazolyl, benzofuranyl,isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl,benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl,purinyl, quinolinyl, isoquinolinyl, quinazolinyl, or quinoxalinyl.

The term “heterocycloalkyl” denotes a monovalent saturated or partlyunsaturated mono- or bicyclic ring system of 3 to 9 ring atoms,comprising 1, 2, or 3 ring heteroatoms selected from N, O and S, theremaining ring atoms being carbon. In particular embodiments,heterocycloalkyl is a monovalent saturated monocyclic ring system of 4to 7 ring atoms, comprising 1, 2, or 3 ring heteroatoms selected from N,O and S, the remaining ring atoms being carbon. Examples for monocyclicsaturated heterocycloalkyl are aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl,pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl,azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples forbicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl,quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl,9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, or3-thia-9-aza-bicyclo[3.3.1]nonyl. Examples for partly unsaturatedheterocycloalkyl are dihydrofuryl, imidazolinyl, dihydro-oxazolyl,tetrahydro-pyridinyl, or dihydropyranyl.

A “patient” is a mammal, e.g., a human, mouse, rat, guinea pig, dog,cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus monkey, and the terms “patient” and“subject” are used interchangeably herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body.

The term “treating”, with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating can be curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject, or administering a prodrug derivative or analog of the compoundor pharmaceutically acceptable salt of the compound or composition tothe subject, which can form an equivalent amount of active compoundwithin the subject's body.

The term “optionally substituted,” as used in this disclosure, means asuitable substituent can replace a hydrogen bound to a carbon, nitrogen,or oxygen. When a substituent is oxo (i.e., ═O) then 2 hydrogens on theatom are replaced by a single O. It will be understood by those skilledin the art, with respect to any group containing one or moresubstituents, that such groups are not intended to introduce anysubstitution or substitution patterns that are sterically impractical,synthetically non-feasible and/or inherently unstable. Furthermore,combinations of substituents and/or variables within any of the Formulaerepresented herein are permissible only if such combinations result instable compounds or useful synthetic intermediates wherein stableimplies a reasonable pharmologically relevant half-life at physiologicalconditions.

Dosage and Administration:

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatin capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell-known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilisation from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to a skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polylactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight, and most preferred 1.0 and about 15 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range in oneembodiment would be about 70 mg to 0.7 g per day. The daily dosage canbe administered as a single dosage or in divided dosages, typicallybetween 1 and 5 dosages per day. Generally, treatment is initiated withsmaller dosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect for the individual patient is reached. One of ordinaryskill in treating diseases described herein will be able, without undueexperimentation and in reliance on personal knowledge, experience andthe disclosures of this application, to ascertain a therapeuticallyeffective amount of the compounds of the present invention for a givendisease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

EXAMPLES

The following examples further describe and demonstrate particularembodiments within the scope of the present invention. Techniques andformulations generally are found in Remington's Pharmaceutical Sciences(Mack Publishing Co., Easton, Pa.). The disclosure is furtherillustrated by the following examples, which are not to be construed aslimiting this disclosure in scope or spirit to the specific proceduresherein described. It is to be understood that the examples are providedto illustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Melting points were determined on an Electrothermal 2300 melting pointapparatus. NMR spectra were obtained on a Bruker Avance 400 spectrometerat 400 MHz for ¹H and 100 MHz for ¹³C spectra and are referenced toMe₄Si. Chemical shifts and coupling constants are recorded in units ofppm and Hz, respectively. Low resolution atmospheric pressure chemicalionization mass spectra ([M+H]) of intermediates were measured formethanol solutions on a ThermoFinnigan Surveyor MSQ mass spectrometer.Thin-layer chromatography was carried out on aluminium-backed silica gelplates (Merck 60 F₂₅₄) with visualization of components by UV light (254nm) and/or exposure to I₂. Column chromatography was carried out onsilica gel (Merck 230-400 mesh) unless stated otherwise. Alumina forcolumn chromatography was Merck aluminium oxide 90 (standardised).Analysis of the final test compounds was carried out on an Agilent1200-6110 LCMS system, using the following conditions; Column: SunfrieC-18, 4.6×50 mm; Mobile phase: ACN (0.05% TFA)-water (0.05% TFA);Gradient: 5% ACN to 95% ACN in 1.0 min, hold 1.0 min, total 2.5 min;flow rate: 1.8 mL/min; LC detector: UV 214 nm, 254 nm; MS ([M+H]):atmospheric pressure electrospray ionisation; MS cone voltage: (V)Positive 4000, Negative 3000. All test compounds were determined tohave >95% purity.

Abbreviations

-   ACN acetonitrile-   aq. aqueous-   bd broad doublet-   bs broad singlet-   n-BuLi n-butyllithium-   d doublet-   DCM dichloromethane-   dd doublet of doublets-   ddd doublet of doublet of doublets-   dist. distilled-   DMAP 4-(dimethylamino)pyridine-   DMF dimethylformamide-   DMSO dimethylsulfoxide-   DPPP 1,3-bis(diphenylphosphino)propane-   dq doublet of quartets-   dt doublet of triplets-   Et₂O diethyl ether-   EtOAc ethyl acetate-   h hour-   HPLC high pressure liquid chromatography-   HOAc acetic acid-   m.p. melting point-   MeOH methanol-   mesyl methanesulfonyl-   min minutes-   p pentet-   pd pentet of doublets-   q quartet-   qt quartet of triplets-   r.t. room temperature-   s singlet-   sat. saturated-   sp septet-   t triplet-   TFA trifluoroacetic acid-   TFAA trifluoroacetic anhydride-   THF tetrahydrofuran

I. Preparation of Representative Intermediates of the Invention(6-Bromo-2-methoxyquinolin-3-yl)boronic acid (1)

A solution of 2,2,6,6-tetramethylpiperidine (14.4 mL, 84.8 mmol) in THF(100 mL, dist. Na) at −78° C. was treated with n-BuLi (33 mL, 2.5 M inhexanes, 82.5 mmol), the solution was then warmedδ to −20° C. for 20 minand then cooled to −78° C. A solution of 6-bromo-2-methoxyquinoline(10.0 g, 42.0 mmol) and triisopropylborate (20.0 mL, 87.2 mmol) in THF(100 mL, dist. Na) was added dropwise and the orange solution wasstirred for 3 h at −78° C., warmed to −40° C. and then quenched withsat. aq. NH₄Cl (500 mL). The mixture was diluted with water (1 L) andthe white precipitate was filtered, triturated with hexanes and dried togive 1 (11.17 g, 94%) as a white solid. ¹H NMR (DMSO-d₆) δ 8.44 (s, 1H),8.15-8.18 (m, 3H), 7.76 (dd, J=8.8, 2.3 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H),3.99 (s, 3H). Found: [M−OH+OMe]=296.2.

2,6-Diethoxyisonicotinic acid (2)

Sodium (4.08 g, 177 mmol) was added to anhydrous ethanol (75 mL) andafter the sodium had completely reacted the resulting solution was addedto 2,6-dichloroisonicotinic acid (5.00 g, 29.6 mmol) in a steel reactor.The mixture was heated to 130° C. for 18 h, cooled and evaporated. Theresidue was dissolved in a minimal amount of water and acidified to pH 3with 2M HCl. The solid was filtered and dried to give 2 as a white solid(4.12 g, 66%). ¹H NMR (CDCl₃) δ 6.80 (s, 2H), 4.28 (q, J=6.8 Hz, 2H),3.85 (br, 1H), 1.36 (s, 3H). Found: [M+H]=212.2

2,6-Diethoxy-N-methoxy-N-methylisonicotinamide (3)

Oxalyl chloride (0.73 mL, 8.6 mmol) was added to a suspension of 2 (1.52g, 7.20 mmol) in DCM (50 mL, anhydrous) and DMF (0.20 mL, 2.6 mmol) atr.t. The mixture was stirred at r.t. for 1 h to give a colourlesssolution, which was then cooled to 0° C. N,O-dimethylhydroxylaminehydrochloride (0.77 g, 17.89 mmol) and pyridine (1.92 mL, 23.7 mmol)were added sequentially and the mixture was stirred at r.t. for 18 h,then partitioned between EtOAc and sat. aq. NaHCO₃. Columnchromatography using 3:1 hexanes:EtOAc gave 3 (1.26 g, 69%). ¹H NMR(CDCl₃) δ 6.43 (s, 2H), 4.33 (q, J=7.1 Hz, 2H), 3.59 (br s, 3H), 3.32(s, 3H), 1.39 (t, J=7.1 Hz, 3H). Found: [M+H]=255.1

1-(2,6-Diethoxypyridin-4-yl)-3-(dimethylamino)propan-1-one (4)

Vinylmagnesium bromide (14.6 mL of a 1N solution in THF, 14.6 mmol) wasadded to a solution of 3 (1.23 g, 4.85 mmol) in dry THF (50 mL) at 0° C.The brown solution was warmed to r.t. for 1 h then a solution of 2Ndimethylamine in THF (14.6 mL, 29.2 mmol) and water (10 mL) were added.The solution was stirred at r.t. for 1 h, then partitioned between EtOAcand water. The solution was dried and evaporated to give 4 as a brownoil (1.24 g, 96%). ¹H NMR (CDCl₃) δ 6.71 (s, 2H), 4.34 (q, J=7.1 Hz,2H), 3.05 (t, J=7.0 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.26 (s, 6H), 1.40(t, J=7.0 Hz, 3H). Found: [M+H]=267.2

N,2,6-Trimethoxy-N-methylisonicotinamide (5)

Oxalyl chloride (1.34 mL, 15.8 mmol) was added to a suspension of2,6-dimethoxyisonicotinic acid (2.41 g, 13.2 mmol) in DCM (70 mL) andDMF (0.20 mL, 2.6 mmol) at r.t. The mixture was stirred for 1 h to givea colourless solution which was cooled to 0° C.N,O-dimethylhydroxylamine hydrochloride (1.42 g, 14.6 mmol) and pyridine(3.51 mL, 28.9 mmol) were added sequentially and the mixture was stirredat r.t. for 18 h, then partitioned between EtOAc and sat. aq. NaHCO₃.Column chromatography with hexanes:EtOAc (2:1) gave 5 (2.49 g, 83%). ¹HNMR (CDCl₃) δ 6.47 (s, 2H), 3.93 (s, 6H), 3.58 (br s, 3H), 3.32 (s, 3H).Found: [M+H]=227.2

1-(2,6-Dimethoxypyridin-4-yl)-3-(dimethylamino)propan-1-one (6)

Vinylmagnesium bromide (32 mL of a 1N solution in THF, 32 mmol) wasadded to a solution of 5 (2.45 g, 10.8 mmol) in dry THF (100 mL) at 0°C. The brown solution was warmed to r.t. for 1 h then dimethylamine (32mL of a 2N solution in THF, 64 mmol) and water (30 mL) were added. Thesolution was stirred at r.t. for 1 h, then partitioned between EtOAc andwater. The solution was dried and evaporated and column chromatographywith DCM:MeOH (95:5) eluted impurities while DCM:MeOH (9:1) gave 6 as anoil (0.81 g, 31%). ¹H NMR (CDCl₃) δ 6.74 (s, 2H), 3.95 (s, 6H), 3.06 (t,J=7.0 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.27 (s, 6H). Found: [M+H]=239.1

3-((2,4-Dimethoxybenzyl)(methyl)amino)-1-(2,6-dimethoxypyridin-4-yl)propan-1-one(7)

Vinylmagnesium bromide (17.7 mL of a 1N solution in THF, 17.7 mmol) wasadded to a solution of 5 (2.00 g, 8.84 mmol) in dry THF (30 mL) at 0° C.The brown solution was warmed to r.t. for 1 h then a solution ofN-methyl-2,4-dimethoxybenzylamine (4.00 g, 22.0 mmol) in THF (10 mL),and water (10 mL) were added. The solution was stirred at r.t. for 1 h,then partitioned between EtOAc and water. The solution was dried andevaporated to give a brown oil, which was chromatographed. Elution withEtOAc/hexanes gave fore fractions, then elution with EtOAc gave 7 (2.27g, 68%) as a light yellow oil. ¹H NMR (CDCl₃) δ 7.13 (d, J=8.9 Hz, 1H),6.73 (s, 2H), 6.44-6.41 (m, 2H), 3.59 (s, 6H), 3.88 (s, 3H), 3.53 (s,3H), 3.50 (s, 2H), 3.12 (t, J=7.0 Hz, 1H), 2.84 (t, J=7.0 Hz, 2H), 2.26(s, 3H). Found: [M+H]=375.3

6-Bromo-3-(2-fluoro-3-methoxybenzyl)-2-methoxyquinoline (8)

To a mixture of 1 (1.50 g, 5.32 mmol) and 2-fluoro-3-methoxybenzylbromide (5.59 mmol) in 1,2-dimethoxyethane (25 mL) in a sealed tube wasadded 2M Na₂CO₃ solution (5 mL) and the mixture was degassed under N₂for 15 min, then Pd(PPh₃)₄ (0.307 g, 0.27 mmol) was added and themixture heated at 90° C. for 4 h. The reaction mixture was cooled tor.t., water (100 mL) was added followed by extraction with EtOAc (2×125mL). The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated to give a yellow residue. Purification by flash columnchromatography using hexanes-EtOAc (100:0 to 95:5) gave 8 as acolourless oil which solidified to give a white powder (1.16 g, 58%). ¹HNMR (CDCl₃) δ 7.75 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.61 (dd,J=8.9, 2.2 Hz, 1H), 7.01 (dt, J=8.1, 1.5 Hz, 1H), 6.88 (dt, J=8.1, 1.5Hz, 1H), 6.78 (dt, J=8.1, 1.5 Hz, 1H), 4.09 (s, 3H), 4.05 (s, 2H), 3.90(s, 3H). Found: [M+H]=376.2

6-Bromo-3-(3-fluorobenzyl)-2-methoxyquinoline (9)

Reaction of 1 with 3-fluorobenzyl bromide as described above forpreparation of 8 gave 9 as a white solid after chromatography (88%). ¹HNMR (CDCl₃) δ 7.77 (d, J=2.2 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.63 (dd,J=8.9, 2.2 Hz, 1H), 7.52 (br s, 1H), 7.30-7.24 (m, 1H), 7.01 (bd d,J=7.7 Hz, 1H), 6.96-6.90 (m, 2H), 4.07 (s, 3H), 3.98 (s, 2H). Found:[M+H]=346.2

6-Bromo-2-methoxy-3-(3-methylbenzyl)quinoline (10)

Reaction of 1 with 3-methylbenzyl bromide as described above forpreparation of 8 gave 10 as a white solid after chromatography (73%). ¹HNMR (CDCl₃) δ 7.76 (d, J=2.2 Hz, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.60 (dd,J=8.8, 2.2 Hz, 1H), 7.48 (br s, 1H), 7.21 (dd, J=7.7, 7.8 Hz, 1H),7.09-7.02 (m, 3H), 4.08 (s, 3H), 3.99 (s, 2H). Found: [M+H]=342.1

6-Bromo-3-(2,3-dimethoxybenzyl)-2-methoxyquinoline (11)

A stirred mixture of 1 (1.63 g, 5.79 mmol), 2,3-dimethoxybenzyl bromide(1.60 g, 6.95 mmol) and Cs₂CO₃ (3.78 g, 11.50 mmol)) in toluene (20 mL)and DMF (10 mL) was deoxygenated by bubbling nitrogen gas through it for10 min. Pd(PPh₃)₄ (0.33 g, 0.29 mmol) was then added and the mixture wasstirred under an atmosphere of nitrogen at 90° C. for 5 h. The mixturewas diluted with EtOAc and washed with water, then brine. The extractwas dried over Na₂SO₄ and the solvent was removed under reducedpressure. The product was chromatographed. Elution with 0-4%EtOAc/hexanes gave the product 11 as a white solid (1.26 g, 56%), whichcrystallised from methanol as colourless microneedles, m.p. 93° C. ¹HNMR (CDCl₃) δ 7.72 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.59 (dd,J=8.9, 2.2 Hz, 1H), 7.44 (br s, 1H), 7.01 (t, J=7.0 Hz, 1H), 6.86 (dd,J=8.2, 1.4 Hz, 1H), 6.75 (dd, J=7.7, 1.4 Hz, 1H), 4.10 (s, 3H), 4.04 (s,2H), 3.89 (s, 3H), 3.77 (s, 3H). Found: [M+H]=388.3

2,5-Dimethylthiophene-3-carbaldehyde (12)

A solution of 2,5-dimethylthiophene (7.80 g, 69.5 mmol) in DCM (15 mL)and a solution of dichloromethoxymethane (10.40 g, 90.5 mmol) in DCM (15mL) were added simultaneously to a solution of TiCl₄ (19.1 mL, 174 mmol)in DCM (20 mL) keeping the temperature of the solution below 5° C. Themixture was stirred at 0° C. for 2 h, warmed to r.t. over 30 min thenpoured onto ice acidified with conc. HCl (20 mL). The mixture waspartitioned between DCM and water, and the organic layer was washed withwater, dried and evaporated. Kugelrohr distillation (membrane pump,kugelrohr set to approximately 175° C.) gave 12 as a colourless liquid(5.81 g, 60%). ¹H NMR (CDCl₃) δ 9.93 (s, 1H), 7.00 (d, J=1.1 Hz, 1H),2.70 (s, 3H), 2.40 (d, J=0.4 Hz, 3H). Found: [M+H]=141.1

(6-Bromo-2-methoxyquinolin-3-yl)(2,5-dimethylthiophen-3-yl)methanol (13)

A solution of 2,2,6,6-tetramethylpiperidine (1.89 mL, 11.1 mmol) in dryTHF (12 mL) was cooled to −40° C., and n-BuLi (4.45 mL of a 2.5Nsolution in hexane, 11.1 mmol) was added and the solution was stirred at−40° C. for 15 min, then cooled to −78° C. A solution of6-bromo-2-methoxyquinoline (2.20 g, 9.28 mmol) in THF (10 mL) was addeddropwise, and the orange solution was stirred at −78° C. for 1.5 h, thena solution of 12 (1.30 g, 9.27 mmol) in THF (10 mL) was added. Themixture was stirred at −78° C. for 3 h, then acetic acid (1.60 mL, 28.0mmol) was added and the solution was allowed to warm to r.t. The mixturewas partitioned between EtOAc and water, and the organic fraction wasdried and evaporated. Chromatography with DCM:hexanes (1:3) elutedstarting materials, then elution with DCM:hexanes (1:1) gave 13 as awhite solid (1.97 g, 56%). ¹H NMR (CDCl₃) δ 7.93 (s, 1H), 7.88 (d, J=2.1Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.65 (dd, J=8.4, 2.1 Hz, 1H), 6.51 (d,J=1.0 Hz, 1H), 6.04 (dd, J=3.3, 0.8 Hz, 1H), 4.07 (s, 3H), 2.67 (d,J=3.4 Hz, 1H), 2.43 (s, 3H), 2.34 (s, 3H). Found: [M+H]=378.2

6-Bromo-3-((2,5-dimethylthiophen-3-yl)methyl)-2-methoxyquinoline (14)

Triethylsilane (6.8 mL, 42.1 mmol) was added to a solution of 13 (1.99g, 5.26 mmol) and TFA (3.9 mL, 52.5 mmol) in DCM (50 mL) at 0° C., andthe solution was stirred for 0.5 h at 0° C. then at r.t. for 2 h. Thesolution was cooled to 0° C., quenched with sat. aq. NaHCO₃ andpartitioned between DCM and water. Column chromatography (1:3DCM:hexanes) gave 14 as a white solid (1.70 g, 89%). ¹H NMR (CDCl₃) δ7.76 (d, J=2.2 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.61 (dd, J=8.9, 2.2 Hz,1H), 7.40 br s, 1H), 6.42 (s, 1H), 4.10 (s, 3H), 3.83 (s, 2H), 2.39 (s,3H), 2.31 (s, 3H). Found: [M+H]=362.2

(6-Bromo-2-methoxyquinolin-3-yl)(5-methylthiophen-2-yl)methanol (15)

A solution of 2,2,6,6-tetramethylpiperidine (3.5 mL, 20.6 mmol) in dryTHF (20 mL) was cooled to −40° C., and n-BuLi (8.0 mL of a 2.5N solutionin hexanes, 20 mmol) was added and the solution was stirred at −40° C.for 15 min, then cooled to −78° C. A solution of6-bromo-2-methoxyquinoline (4.00 g, 16.8 mmol) in THF (20 mL) was addeddropwise and the orange solution was stirred at −78° C. for 1.5 h. Asolution of 5-methylthiophene-2-carbaldehyde (1.12 g, 16.8 mmol) in THF(10 mL) was added. The mixture was stirred at −78° C. for 3 h, thenacetic acid (2.9 mL, 50.7 mmol) was added and the solution was allowedto warm to r.t. The mixture was partitioned between EtOAc and water andthe organic fraction was dried and evaporated. Chromatography withDCM:hexanes (1:3) eluted unreacted starting materials, then elution withDCM:hexanes (1:1) gave 15 as a white solid (3.37 g, 55%). ¹H NMR (CDCl₃)δ 8.00 (s, 1H), 7.88 (d, J=2.1 Hz, 1H), 7.71 (d, J=8.9 Hz, 1H), 7.66(dd, J=8.9, 2.1 Hz, 1H), 6.72 (d, J=3.4 Hz, 1H), 6.59 (dd, J=3.4, 1.0Hz, 1H), 6.18 (s, 1H), 4.07 (s, 3H), 3.03 (bs, 1H), 2.44 (s, 3H). Found:[M+H]=364.1

6-Bromo-2-methoxy-3-((5-methylthiophen-2-yl)methyl)quinoline (16)

Triethylsilane (13.6 mL, 84 mmol) was added to a solution of 15 (3.75 g,10.3 mmol) and TFA (7.70 mL, 104 mmol) in DCM (100 mL) at 0° C., thenthe solution was stirred for 0.5 h at r.t. and ice water was added. Thesolution was partitioned between sat. aq. NaHCO₃ and DCM and the aqueousfraction was extracted with DCM, the organic fractions were combined andevaporated. Chromatography (1:3 DCM:hexanes to 1:1 DCM:hexanes) gave 16as a white solid (2.83 g, 79%). ¹H NMR (CDCl₃) δ 7.78 (d, J=2.2 Hz, 1H),7.69 (d, J=8.8 Hz, 1H), 7.62 (br s, 1H), 7.61 (dd, J=8.8, 2.2 Hz, 1H),6.65 (d, J=3.3 Hz, 1H), 6.59 (d, J=3.3 Hz, 1H), 4.13 (br s, 2H), 4.10(s, 3H), 2.44 (s, 3H). Found: [M+H]=348.2

6-Bromo-2-methoxy-3-((2-methoxypyridin-3-yl)methyl)quinolone (17)

A mixture of 1 (1.00 g, 3.55 mmol), 3-(chloromethyl)-2-methoxypyridine(0.68 g, 4.31 mmol) and Cs₂CO₃ (2.31 g, 7.09 mmol) in toluene:DMF (60mL, 2:1) was degassed under N₂, then Pd(PPh₃)₄ (0.082 g, 0.071 mmol) wasadded, and the mixture heated at 80° C. for 4 h. The reaction mixturewas cooled to r.t., filtered through a plug of Celite, water (150 mL)was added and extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain a yellow residue.Purification by flash column chromatography using hexanes:EtOAc (9:1)gave 17 as white solid (0.94 g, 74%). ¹H NMR (CDCl₃) δ 8.08 (dd, J=5.0,1.9 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H), 7.61 (dd,J=8.9, 2.2 Hz, 1H), 7.53 (s, 1H), 7.38 (dd, J=7.2, 1.9 Hz, 1H), 6.83(dd, J=7.2, 5.0 Hz, 1H), 4.07 (s, 3H), 3.96 (s, 2H), 3.95 (s, 3H).Found: [M+H]=359.6.

N-Methoxy-N-methyl-2,3-dihydro-1H-indene-4-carboxamide (18)

To a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (4.40 g, 27.5mmol) in DCM (250 mL) was added DMF (0.426 mL) followed by dropwiseaddition of oxalyl chloride (4.19 g, 33.0 mmol). The reaction mixturewas stirred for 1 h, cooled to 0° C., then N,O-dimethylhydroxylaminehydrochloride (2.95 g, 30.3 mmol) and pyridine (7.32 mL, 90.7 mmol) wereadded and the reaction was stirred at r.t. for 18 h. The mixture waspoured onto sat. aqueous NaHCO₃ (150 mL) and extracted with DCM (3×100mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain a yellowish residue. Thecrude product 18 was used in the next step without further purification(5.64 g, 100%). ¹H NMR (CDCl₃) δ 7.21-7.13 (m, 3H), 3.56 (s, 3H), 3.31(s, 3H), 2.98-2.91 (m, 4H), 2.11-2.04 (m, 2H). Found: [M+H]=206.5.

1-(2,3-Dihydro-1H-inden-4-yl)-3-(dimethylamino)propan-1-one (19)

To a solution of 18 (5.64 g, 27.5 mmol) in THF (150 mL) at 0° C. wasadded vinylmagnesium bromide (1M solution in THF, 57.7 mL, 57.7 mmol)and the solution was stirred for 3.5 h at 0° C. Dimethylamine (2Msolution in THF, 57.7 mL, 115.5 mmol) was added to the reaction mixturefollowed by water (60 mL). After 30 minutes stirring at r.t., thereaction mixture was concentrated under reduced pressure to obtain abrownish residue. This was extracted with EtOAc (3×200 mL). The combinedorganic layers were washed with brine (100 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to obtain 19 as brownoil (5.66 g, 95%). ¹H NMR (CDCl₃) δ 7.66 (d, J=7.8 Hz, 1H), 7.34 (d,J=7.4 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 3.24 (t, J=7.5 Hz, 2H), 3.11 (t,J=7.3 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.72 (t, J=7.3 Hz, 2H), 2.27 (s,6H), 2.04 (t, J=7.5 Hz, 2H). Found: [M+H]=218.6.

(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)methanol (20)

To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid (5.00g, 28.0 mmol) in THF (150 mL) at 0° C. was added lithium aluminiumhydride (2.13 g, 56.0 mmol) in small portions. The reaction mixture wasstirred at 0° C. for 10 min and stirred for a further 18 h at r.t. Water(150 mL) was added to the reaction mixture which was extracted withEtOAc (2×100 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to obtain 20 as yellow oil (3.22 g, 99%). ¹H NMR (CDCl₃)δ6.87-6.79 (m, 3H), 4.66 (s, 2H), 4.32-4.30 (m, 2H), 4.28-4.25 (m, 2H),2.19 (bs, 1H). Found: [M+H−18]=149.5.

5-(Bromomethyl)-2,3-dihydrobenzo[b][1,4]dioxine (21)

A solution of 20 (3.75 g, 32.3 mmol) in diethyl ether (80 mL) was cooledto 0° C. and phosphorous tribromide (3.67 mL, 38.8 mmol) was addeddropwise. The solution was stirred at 0° C. for 10 min, then at r.t. for1 h. Water (10 mL) was added cautiously to quench the excess of reagentand the mixture was diluted with diethyl ether and washed with water(3×50 mL). The combined organic layers were washed with brine (100 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure toobtain 21 as a brown solid (4.61 g, 62%). ¹H NMR (CDCl₃) δ 6.91-6.77 (m,3H), 4.52 (s, 2H), 4.35-4.33 (m, 2H), 4.29-4.27 (m, 2H). Found:[M+H-Br]=149.5.

6-Bromo-3-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-2-methoxyquinoline(22)

A mixture of 1 (4.42 g, 15.4 mmol), 21 (4.6 g, 20.0 mmol) and Cs₂CO₃(11.54 g, 0.77 mmol) in toluene:DMF (60 mL, 2:1) was degassed under N₂,then Pd(PPh₃)₄ (0.890 g, 0.77 mmol) was added, and the mixture heated at110° C. for 4 h. The mixture was cooled to r.t., filtered through a plugof Celite, water (150 mL) was added and extracted with EtOAc (3×100 mL).The combined organic layers were washed with brine (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to obtain ayellow residue. Purification by flash column chromatography usinghexanes:EtOAc (9:1) gave 22 as white solid (3.1 g, 52%). ¹H NMR (CDCl₃)δ 7.75 (d, J=2.2 Hz, 1H), 7.73-7.70 (m, 1H), 7.61-7.59 (m, 1H), 7.43 (s,1H), 6.84-6.78 (m, 2H), 6.72-6.70 (m, 1H), 4.27-4.22 (m, 4H), 4.10 (s,3H), 3.98 (s, 2H). Found: [M+H]=386.6.

3-Benzyl-6-iodo-2-methoxyquinoline (23)

A solution of 3-benzyl-6-bromo-2-methoxyquinoline (3.00 g, 9.14 mmol) inTHF (7 mL) was cooled to −78° C., then n-BuLi (2M solution incyclohexane, 5.48 mL, 11.0 mmol) was added to give a deep purplesolution. After 60 seconds, iodine (1.74 g, 7.31 mmol) in THF (23 mL)was added and the red solution was stirred at −78° C. for 10 min Water(20 mL) was added to the resultant solution which was extracted withEtOAc (3×30 mL), dried with MgSO₄, filtered and the solvent wasevaporated to give orange oil. MeOH (10 mL) was added to the mixturewhich was sonicated until a white solid formed. The solid was filteredto give 23 as a white solid (1.77 g, 52%). ¹H NMR (CDCl₃) δ 7.96 (d,J=2.0 Hz, 1H), 7.77 (dd, J=8.8, 2.0 Hz, 1H), 7.55 (d, J=8.8 Hz, 1H),7.46 (s, 1H), 7.34-7.22 (m, 5H), 4.08 (s, 3H), 4.02 (s, 2H). Found:[M+H]=376.6.

2,6-Bis(ethylthio)isonicotinic acid (24)

To a suspension of sodium hydride (1.82 g, 45.5 mmol) in DMF (20 mL) at0° C. was added ethanethiol (3.29 mL, 45.5 mmol) dropwise. The milkyfoamy solution was stirred at 0° C. for 10 min 2,6-Dichloroisonicotinicacid (3.17 g, 13.0 mmol) in DMF (5 mL) was added dropwise to thesolution. The mixture was warmed to 50° C. and stirred for 18 h. Water(40 mL) was added to the resultant solution and the pH was adjusted to˜3 using 2M HCl solution. The aqueous solution was extracted with EtOAc(3×30 mL), dried with MgSO₄, filtered and the solvent was evaporated togive 24 as a yellow solid which was used for the next step withoutfurther purification (2.82 g, 89%). ¹H NMR (CDCl₃) δ 7.40 (s, 2H), 3.19(q, J=7.3 Hz, 4H), 1.39 (t, J=7.3 Hz, 6H). Found: [M+H]=244.5.

2,6-Bis(ethylthio)-N-methoxy-N-methylisonicotinamide (25)

To a solution of 24 (3.24 g, 13.3 mmol) in DCM (150 mL) was added DMF(0.206 mL), followed by dropwise addition of oxalyl chloride (1.37 mL,16.0 mmol). The mixture was stirred at r.t. for 2 h, then cooled to 0°C. and N,O-dimethylhydroxylamine hydrochloride (1.43 g, 14.6 mmol)followed by pyridine (3.55 mL, 43.9 mmol) were added and resultingmixture was stirred at r.t. for 18 h. The mixture was poured onto sat.NaHCO₃ (150 mL), extracted with DCM (150 mL) and EtOAc (100 mL). Thecombined organic phase was dried with Na₂SO₄ and concentrated to give ayellow residue. Purification by flash column chromatography usinghexanes:EtOAc (1:1) gave 25 as colourless oil (3.65 g, 96%). ¹H NMR(CDCl₃) δ 7.02 (s, 2H), 3.56 (s, 3H), 3.32 (s, 3H), 3.19 (q, J=7.3 Hz,4H), 1.37 (t, J=7.3 Hz, 6H). Found: [M+H]=287.5.

1-(2,6-Bis(ethylthio)pyridin-4-yl)-3-(dimethylamino)propan-1-one (26)

To a solution of 25 (3.65 g, 12.7 mmol) in THF (150 mL) at 0° C. wasadded vinylmagnesium bromide (1M solution in THF, 31.5 mL, 31.5 mmol)which was then stirred at 0° C. for 4 h. Dimethylamine (2M solution inTHF, 31.5 mL, 63.0 mmol) was added followed by water (60 mL). After 30minutes stirring at r.t., the reaction mixture was concentrated underreduced pressure to obtain a brownish residue. This was extracted withEtOAc (3×200 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a brown oil. Purification by flash columnchromatography using EtOAc:MeOH (9:1) gave 26 as a yellow oil (2.51 g,66%). ¹H NMR (CDCl₃) δ 7.24 (s, 2H), 3.20 (q, J=7.4 Hz, 4H), 3.03 (t,J=7.1 Hz, 2H), 2.71 (t, J=7.2 Hz, 2H), 2.26 (s, 6H), 1.38 (t, J=7.4 Hz,6H). Found: [M+H]=299.6.

2,6-Bis(methylthio)isonicotinic acid (27)

To a solution of 2,6-dichloroisonicotinic acid (4.00 g, 20.8 mmol) inDMF (40 mL) at 0° C. was added sodium thiomethoxide (4.38 g, 65.5 mmol).The reaction mixture was stirred at 150° C. for 18 h. Water (40 mL) wasadded to the resultant solution and the pH was adjusted to ˜3 using 2MHCl solution. The aqueous solution was extracted with EtOAc (3×40 mL),dried with MgSO₄, filtered and concentrated under reduced pressure togive 27 as an orange solid, which was recrystallized from methanol (4.01g, 90%). ¹H NMR (CDCl₃) δ 7.44 (s, 2H), 2.61 (s, 6H). Found:[M+H]=216.5.

N-Methoxy-N-methyl-2,6-bis(methylthio)isonicotinamide (28)

To a solution of 27 (5.03 g, 23.4 mmol) in DCM (200 mL) was added DMF(0.362 mL), followed by dropwise addition of oxalyl chloride (2.41 mL,28.0 mmol). The mixture was stirred at r.t. for 2 h, cooled to 0° C. andN,O-dimethylhydroxylamine hydrochloride (2.51 g, 25.7 mmol) followed bypyridine (6.22 mL, 77.1 mmol) were added and resulting mixture wasstirred at r.t. for 18 h. The mixture was poured onto sat NaHCO₃ (150mL), extracted with DCM (150 mL) and EtOAc (100 mL). The organic phasewas dried with Na₂SO₄ and concentrated to give 28 as yellow oil, whichwas used without further purification for the next step (4.96 g, 82%).¹H NMR (CDCl₃) δ 7.04 (s, 2H), 3.56 (s, 3H), 3.33 (s, 3H), 2.60 (s, 6H).Found: [M+H]=259.5.

1-(2,6-Bis(methylthio)pyridin-4-yl)-3-(dimethylamino)propan-1-one (29)

To a solution of 28 (4.96 g, 19.2 mmol) in THF (90 mL) at 0° C. wasadded vinylmagnesium bromide (1M solution in THF, 40.3 mL, 40.3 mmol)and the solution was stirred at 0° C. for 1 h. Dimethylamine (2Msolution in THF, 40.3 mL, 80.6 mmol) was added followed by water (60mL). After 30 minutes stirring at r.t., the reaction mixture wasconcentrated under reduced pressure to obtain a brownish residue. Thiswas extracted with EtOAc (3×200 mL). The combined organic layers werewashed with brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give 29 as a brown oil (4.87 g, 94%). ¹H NMR(CDCl₃) δ 7.26 (s, 2H), 3.04 (t, J=7.0 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H),2.61 (s, 6H), 2.26 (s, 6H). Found: [M+H]=271.6.

6-Bromo-3-(2-fluoro-3-methylbenzyl)-2-methoxyquinoline (30)

A mixture of 1 (3.00 g, 10.5 mmol),1-(bromomethyl)-2-fluoro-3-methylbenzene (4.24 g, 20.9 mmol) and Cs₂CO₃(7.87 g, 24.2 mmol) in toluene:DMF (60 mL, 2:1) was degassed under N₂,then Pd(PPh₃)₄ (0.607 g, 0.525 mmol) was added, and the mixture washeated at 90° C. for 2 h. The reaction mixture was cooled to r.t.,filtered through a plug of Celite, water (150 mL) was added and themixture was extracted with EtOAc (3×100 mL). The organic layer waswashed with brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to obtain a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (9:1) gave 30 as a white solid(2.87 g, 76%). ¹H NMR (CDCl₃) δ 7.75 (d, J=2.2 Hz, 1H), 7.67 (d, J=8.8Hz, 1H), 7.60 (dd, J=8.9, 2.2 Hz, 1H), 7.50 (s, 1H), 7.11-6.96 (m, 3H),4.09 (s, 3H), 4.03 (s, 2H), 2.28 (d, J=2.1 Hz, 3H). Found: [M+H]=360.6.

2-Methoxy-6-(methylthio)isonicotinic acid (31)

To a mixture of methyl 2-methoxy-6-(methylthio)isonicotinate (WO2010/036632) (2.07 g, 9.71 mmol) in MeOH:THF:H₂O (60 mL, 1:1:1) wasadded lithium hydroxide (0.697 g, 29.1 mmol). The reaction mixture wasstirred at r.t. for 24 h. The solvent was removed under reducedpressure, water (50 mL) was added and the mixture was washed with EtOAc(50 mL) which was discarded. 2M HCl (50 mL) was added to the aqueouslayer, which was extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain 31 as a white solid (1.70g, 88%). ¹H NMR (DMSO-d₆) δ 13.67 (s, 1H), 7.22 (d, J=0.92 Hz, 1H), 6.86(d, J=0.92 Hz, 1H), 3.90 (s, 3H), 2.55 (s, 3H). Found: [M+H]=200.5.

N,2-Dimethoxy-N-methyl-6-(methylthio)isonicotinamide (32)

To a solution of 31 (1.70 g, 8.53 mmol) in DCM (200 mL) was added DMF(0.13 mL), followed by dropwise addition of oxalyl chloride (0.88 mL,10.2 mmol). The mixture was stirred at r.t. for 2 h. The reactionmixture was cooled to 0° C. and N,O-dimethylhydroxylamine hydrochloride(0.915, 9.38 mmol) followed by pyridine (2.27 mL, 28.2 mmol) were addedand resulting mixture was stirred at r.t. for 18 h. The mixture waspoured onto sat. NaHCO₃ (150 mL) and extracted with DCM (150 mL) andEtOAc (100 mL). The combined organic phase was dried with Na₂SO₄ andconcentrated to give a yellow residue. Purification by flash columnchromatography using hexanes:EtOAc (4:1) gave 32 as yellow oil (2.07 g,99%). ¹H NMR (CDCl₃) δ 6.93 (d, J=0.72 Hz, 1H), 6.59 (s, 1H), 3.97 (s,3H), 3.57 (s, 3H), 3.32 (s, 3H), 2.57 (s, 3H). Found: [M+H]=243.5.

3-(Dimethylamino)-1-(2-methoxy-6-(methylthio)pyridin-4-yl)propan-1-one(33)

To a solution of 32 (2.07 g, 8.54 mmol) in THF (100 mL) at 0° C. wasadded vinylmagnesium bromide (1M solution in THF, 17.9 mL, 17.9 mmol)and the solution was stirred at 0° C. for 3 h. Dimethylamine (2Msolution in THF, 17.9 mL, 35.9 mmol) was added followed by water (40mL). After 30 minutes stirring at r.t. the reaction mixture wasconcentrated under reduced pressure to obtain a brownish residue. Thiswas extracted with EtOAc (3×200 mL). The combined organic layers werewashed with brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give 33 as a brown oil (2.17 g, 99%). ¹H NMR(CDCl₃) δ 7.19 (d, J=1.2 Hz, 1H), 6.82 (d, J=1.1 Hz, 1H), 3.98 (s, 3H),3.04 (t, J=7.0 Hz, 2H), 2.72 (t, J=7.3 Hz, 2H), 2.58 (s, 3H), 2.27 (s,6H). Found: [M+H]=255.6.

Methyl 2-(difluoromethoxy)-6-methoxyisonicotinate (34)

To a solution of methyl 2-hydroxy-6-methoxyisonicotinate (WO2009/083553) (3.00 g, 16.4 mmol) in DMF (40 mL) was added sodiumchlorodifluoroacetate (7.50 g, 49.2 mmol) and K₂CO₃ (2.73 g, 21.3 mmol).The reaction mixture was stirred at 80° C. for 72 h, then washed withwater (50 mL) and extracted with EtOAc (3×30 mL). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain a yellow residue.Purification by flash column chromatography using hexanes:EtOAc (1:1)gave 34 as a white solid (2.02 g, 52%). ¹H NMR (CDCl₃) δ 7.40 (t,J=73.0, 1H), 7.10 (d, J=1.0 Hz, 1H), 7.00 (d, J=1.0 Hz, 1H), 3.94 (s,3H), 3.93 (s, 3H). Found: [M+H]=234.5.

2-(Difluoromethoxy)-6-methoxyisonicotinic acid (35)

To a solution of 34 (2.02 g, 8.66 mmol) in MeOH:THF:H₂O (60 mL, 1:1:1)was added lithium hydroxide (0.62 g, 26.0 mmol) and the reaction mixturewas stirred at r.t. for 72 h. The solvent was removed under reducedpressure, water (50 mL) was added and the mixture was washed with EtOAc(50 mL) which was discarded. 2M HCl (50 mL) was added to the aqueouslayer, which was extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (100 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain 35 as a white solid (1.90g, 99%). ¹H NMR (DMSO-d₆) δ 13.85 (bs, 1H), 7.76 (t, J=72.5 Hz, 1H),7.03 (d, J=0.96 Hz, 1H), 6.95 (d, J=0.92 Hz, 1H), 3.91 (s, 3H). Found:[M+H]=220.6.

2-(Difluoromethoxy)-N,6-dimethoxy-N-methylisonicotinamide (36)

To a solution of 35 (1.70 g, 8.53 mmol), hydroxybenzotriazole (1.29 g,9.54 mmol), N,O-dimethylhydroxylamine hydrochloride (1.27 g, 13.0 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.48 g, 9.54 mmol) inDCM (50 mL) was added DMF (4.83 mL, 34.7 mmol). The reaction mixture wasstirred at r.t for 24 h. The reaction mixture was washed with water (100mL) and extracted with DCM (3×50 mL). The organic phase was dried withNa₂SO₄ and concentrated to give a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (1:1) gave 36 as a yellow oil(1.85 g, 81%). ¹H NMR (CDCl₃) δ 7.41 (t, J=73.1 Hz, 1H), 6.73 (d, J=0.68Hz, 1H), 6.65 (d, J=0.64 Hz, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.34 (s,3H). Found: [M+H]=263.5.

1-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-3-(dimethylamino)propan-1-one(37)

To a solution of 36 (1.85 g, 7.06 mmol) in THF (100 mL) at 0° C. wasadded vinylmagnesium bromide (1M solution in THF, 14.8 mL, 14.8 mmol)and the solution stirred at 0° C. for 3 h. Dimethylamine (2M solution inTHF, 14.8 mL, 29.7 mmol) was added followed by water (40 mL). After 30minutes stirring at r.t., the reaction mixture was concentrated underreduced pressure to obtain a brownish residue. This was extracted withEtOAc (3×200 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give 37 as a brown oil (1.92 g, 99%). ¹H NMR (CDCl₃) δ 7.40(t, J=73.0 Hz, 1H), 6.97 (d, J=1.1 Hz, 1H), 6.89 (d, J=1.1 Hz, 1H), 3.95(s, 3H), 3.07 (t, J=7.0 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 2.27 (s, 6H).Found: [M+H]=275.6.

(2,6-Bis(methylthio)pyridin-4-yl)methanol (38)

To a solution of 27 (6.12 g, 28.4 mmol) in THF (100 mL, dist. Na) at 0°C. was added borane dimethyl sulfide complex (8.09 mL, 85.3 mmol)followed by trimethyl borate (9.68 mL, 85.3 mmol). The reaction mixturewas warmed to r.t. and stirred for 21 h. The reaction mixture was cooledto 0° C., MeOH (50 mL) was added to quench the reaction and solvent wasremoved under reduced pressure. The residue was washed with water (100mL), extracted with EtOAc (3×50 mL) and the organic phase was dried withNa₂SO₄ and concentrated to give a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (4:1) gave 38 as a white solid(4.56 g, 80%). ¹H NMR (CDCl₃) δ 6.87 (t, J=0.7 Hz, 2H), 4.61 (s, 2H),2.58 (s, 6H). Found: [M+H]=202.5.

4-(Bromomethyl)-2,6-bis(methylthio)pyridine (39)

To a solution of 38 (5.26 g, 26.1 mmol) in DCM (300 mL) at 0° C. wasadded phosphorous tribromide (2.97 mL, 31.4 mmol). The reaction mixturewas stirred at r.t. for 18 h and solvent was removed under reducedpressure. The residue was diluted with DCM (100 mL) and quenched withice-water (100 mL), then the organic phase was washed with sat. aq.NaHCO₃, dried with Na₂SO₄ and concentrated to give a yellow residue.Purification by flash column chromatography using hexanes:EtOAc (6:1)gave 39 as white solid (3.44 g, 50%). ¹H NMR (CDCl₃) δ 6.86 (s, 2H),4.23 (s, 2H), 2.58 (s, 6H). Found: [M+H]=264.4.

3-((2,6-Bis(methylthio)pyridin-4-yl)methyl)-6-bromo-2-methoxyquinoline(40)

A mixture of 1 (4.31 g, 15.0 mmol), 39 (3.44 g, 15.0 mmol) and Cs₂CO₃(11.24 g, 34.5 mmol) in toluene:DMF (60 mL, 2:1) was degassed under N₂,then Pd(PPh₃)₄ (0.867 g, 0.75 mmol) was added and the mixture was heatedat 90° C. for 2 h. The reaction mixture was cooled to r.t., filteredthrough a plug of Celite, water (150 mL) was added and the mixture wasextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (9:1) gave 40 as a white solid(2.91 g, 46%). ¹H NMR (CDCl₃) δ 7.80 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 7.64 (dd, J=8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.72 (s, 2H), 4.05(s, 3H), 3.87 (s, 2H), 2.57 (s, 6H). Found: [M+H]=421.8.

(2,3-Dihydro-1H-inden-4-yl)methanol (41)

To a solution of 2,3-dihydro-1H-indene-4-carboxylic acid (6.12 g, 28.4mmol) in THF (100 mL, dist. Na) at 0° C. was added lithium aluminiumhydride (8.09 mL, 85.3 mmol) in small portions. The reaction mixture wasstirred at 0° C. for 30 min and then at r.t. for a further 24 h. Thereaction mixture was washed with water (100 mL) and extracted with EtOAc(3×50 mL). The organic phase was dried with Na₂SO₄ and concentratedunder reduced pressure to obtain 41 as a yellow oil (2.45 g, 99%). ¹HNMR (CDCl₃) δ 7.22-7.12 (m, 3H), 4.67 (s, 2H), 2.93 (t, J=7.6 Hz, 2H),2.91 (t, J=7.4 Hz, 2H), 2.09 (p, J=7.6 Hz, 2H). Found: [M+H−18]=131.5.

4-(Chloromethyl)-2,3-dihydro-1H-indene (42)

To a solution of 41 (4.33 g, 36.4 mmol) in DCM (50 mL) at 0° C. wasadded thionyl chloride (2.45 g, 16.5 mmol). The reaction mixture wasstirred at r.t. for 24 h and solvent was removed under reduced pressure.The residue was diluted with DCM (100 mL) and quenched with ice-water(100 mL). The organic phase was washed with sat. aq. NaHCO₃, dried withNa₂SO₄ and concentrated to give a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (1:1) gave 42 as a colourlessoil (2.36 g, 86%). ¹H NMR (CDCl₃) δ 7.22-7.13 (m, 3H), 4.59 (s, 2H),2.99 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.11 (p, J=7.6 Hz, 2H).Found: [M+H]=167.5.

6-Bromo-3-((2,3-dihydro-1H-inden-4-yl)methyl)-2-methoxyquinoline (43)

A mixture of 1 (3.69 g, 12.9 mmol), 42 (2.36 g, 14.2 mmol) and Cs₂CO₃(9.67 g, 29.7 mmol) in toluene:DMF (60 mL, 2:1) was degassed under N₂,then Pd(PPh₃)₄ (0.745 g, 0.645 mmol), was added and the mixture washeated at 90° C. for 3 h. The reaction mixture was cooled to r.t.,filtered through a plug of Celite, water (150 mL) was added the mixturewas extracted with EtOAc (3×100 mL). The combined organic layers werewashed with brine (100 mL), dried over Na₂SO₄, filtered and concentratedunder reduced pressure to obtain a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (9:1) gave 43 as a yellow oil(4.70 g, 99%). ¹H NMR (CDCl₃) δ 7.71 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.9Hz, 1H), 7.60 (dd, J=8.9, 2.2 Hz, 1H), 7.33 (s, 1H), 7.18-7.11 (m, 2H),6.95 (d, J=7.2 Hz, 1H), 4.11 (s, 3H), 3.98 (s, 2H), 2.96 (t, J=7.5 Hz,2H), 2.79 (t, J=7.4 Hz, 2H), 2.04 (p, J=7.6 Hz, 2H). Found: [M+H]=368.5.

(5,6,7,8-Tetrahydronaphthalen-1-yl)methanol (44)

To a solution of 1-tetrahydronaphthoic acid (5.70 g, 32.3 mmol) in THF(100 mL, dist. Na) at 0° C. was added lithium aluminium hydride (2.46 g,64.7 mmol) in small portions. The reaction mixture was stirred at 0° C.for 30 min and then stirred for further 24 h at r.t. The reactionmixture was washed with water (100 mL) and extracted with EtOAc (3×50mL). The organic phase was dried with Na₂SO₄ and concentrated underreduced pressure to obtain 44 as colourless oil (5.23 g, 99%). ¹HNMR(CDCl₃) δ 7.18 (d, J=7.4 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 7.05 (d, J=7.6Hz, 1H), 4.67 (s, 2H), 2.80 (t, J=6.2 Hz, 2H), 2.76 (t, J=6.4 Hz, 2H),1.88-1.77 (m, 4H). Found: [M+H−18]=145.5.

5-(Chloromethyl)-1,2,3,4-tetrahydronaphthalene (45)

To a solution of 44 (5.24 g, 32.3 mmol) in DCM (200 mL) at 0° C. wasadded thionyl chloride (8.45 g, 71.1 mmol). The reaction mixture wasstirred at r.t. for 24 h, then solvent was removed under reducedpressure. The residue was diluted with DCM (100 mL) and quenched withice-water (100 mL). The organic phase was washed with sat. aq. NaHCO₃,dried with Na₂SO₄ and concentrated to give 45 as a brown oil (3.25 g,56%). ¹H NMR (CDCl₃) δ 7.16-7.05 (m, 3H), 4.59 (s, 2H), 2.86 (t, J=6.3Hz, 2H), 2.79 (t, J=6.4 Hz, 2H), 1.88-1.77 (m, 4H). Found: [M+H]=181.6.

6-Bromo-2-methoxy-3-((5,6,7,8-tetrahydronaphthalen-1-yl)methyl)quinolone(46)

A mixture of 1 (4.69 g, 16.4 mmol), 45 (3.25 g, 18.0 mmol) and Cs₂CO₃(12.29 g, 37.7 mmol) in toluene:DMF (60 mL, 2:1) was degassed under N₂,then Pd(PPh₃)₄ (0.948 g, 0.82 mmol) was added and the mixture was heatedat 90° C. for 3 h. The reaction mixture was cooled to r.t., filteredthrough a plug of Celite, water (150 mL) was added and the mixture wasextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine (100 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to obtain a yellow residue. Purification by flashcolumn chromatography using hexanes:EtOAc (9:1) gave 46 as a white solid(4.64 g, 74%). ¹H NMR (CDCl₃) δ 7.71-7.69 (m, 2H), 7.60 (dd, J=8.9, 2.2Hz, 1H), 7.23 (s, 1H), 7.12-7.04 (m, 2H), 6.92 (d, J=6.9 Hz, 1H), 4.11(s, 3H), 3.96 (s, 2H), 2.83 (bs, 2H), 2.57 (bs, 2H), 1.76 (p, J=3.5 Hz,4H). Found: [M+H]=382.1.

6-Fluoro-N-methoxy-N-methylnicotinamide (47)

To a suspension of 6-fluoronicotinic acid (2.00 g, 14.20 mmol) inanhydrous DCM (56 mL) was added 8 drops of anhydrous DMF under nitrogenflow. Oxalyl chloride (1.4 mL, 17.0 mmol) was added slowly.Effervescence was observed throughout addition. The resultant mixturewas stirred at room temperature for 1.5 hours by which time it hadbecome clear. The mixture was cooled to 2° C., N,O-dimethylhydroxylaminehydrochloride (1.52 g, 15.60 mmol) was added, followed by anhydrouspyridine (2.5 mL, 31.2 mmol). The mixture was stirred from 2° C. to r.t.overnight. The mixture was treated with sat. aq. NaHCO₃ solution untilgas evolution ceased. The organic layer was collected. The aqueous phasewas further extracted with EtOAc (2×). The organic extract was washedwith brine, dried (MgSO₄) and concentrated in vacuo to furnish the crudeproduct. Flash chromatography of the crude product using 1-3% MeOH inDCM as eluents afforded the product 47 as a light brown oil. Yield=1.96g, 75%. ¹H NMR (CDCl₃) δ 8.66 (1H, d, J=2.4 Hz), 8.19 (1H, ddd, J=2.4,3.6, 8.8 Hz), 7.0 (1H, ddd, J=0.4, 2.8, 8.8 Hz), 3.57 (3H, s), 3.40 (3H,s).

6-(Diethylamino)nicotinaldehyde (48)

To a glass pressure tube was charged a solution of 47 (2.13 g, 11.60mmol) and diethylamine (2.4 mL, 23.20 mmol) in anhydrous acetonitrile(12 mL). The mixture was sealed in the tube and refluxed for 3 hours.The solvent was removed and the residue was treated with sat. aq. NaHCO₃solution and extracted with DCM (5×). The combined extract was washedwith brine, dried (MgSO₄) and concentrated to yield the crude product asa brown oil. ¹H NMR analysis of the crude product indicated a 10:7mixture of product and starting material. The mixture was submitted tothe above reaction conditions again and the reaction left to proceedovernight. Work up as above gave the crude product as a brown oil (2.58g), which was used directly in the next step. ¹H NMR analysis confirmedthe identity and purity of the diethylaminopyridine intermediate. ¹H NMR(CDCl₃) δ 8.70 (1H, d, J=2.4 Hz), 7.90 (1H, dd, J=2.4, 9.1 Hz), 6.44(1H, d, J=9.1 Hz), 3.62 (3H, s), 3.56 (4H, q, J=7.1 Hz), 3.35 (3H, s),1.20 (6H, t, J=7.1 Hz). The intermediate adduct (2.58 g) was dissolvedin freshly distilled THF (40 mL). To the solution was added at −78° C.under nitrogen lithium aluminium hydride (0.31 g, 8.15 mmol) in oneportion. The mixture was maintained at −78° C. for 30 min, then at 2° C.for 75 min. The mixture was quenched with water dropwise, until gasevolution ceased. 1M Sodium hydroxide solution (16 mL) was added, theresultant yellow mixture was stirred for 30 min. The aqueous mixture wasextracted with EtOAc (2×), and the combined extract was washed withbrine, dried (MgSO₄) and concentrated in vacuo to give the crude productas a yellow oil. Flash chromatography of the crude product using 4:1then 3:1 mixtures of hexanes/EtOAc as eluent afforded the product 48 asa colourless oil. Yield=1.42 g, 75%. ¹H NMR (CDCl₃) δ 9.74 (1H, d, J=0.3Hz), 8.53 (1H, dd, J=0.04, 2.3 Hz), 7.88 (1H, dd, J=0.4, 2.3 Hz), 6.51(1H, d, J=9.2 Hz), 3.60 (4H, q, J=7.0 Hz), 1.23 (6H, t, J=7.1 Hz).Found: [M+H]=179.6

(6-Bromo-2-methoxyquinolin-3-yl)(6-(diethylamino)pyridin-3-yl)methanol(49)

n-BuLi (4.4 mL, 8.760 mmol) was added at −30° C. under nitrogen to asolution of freshly distilled 2,2,6,6-tetramethylpiperidine (1.6 mL,9.557 mmol) in freshly distilled THF (13 mL). The mixture was maintainedat about −30° C. for 15 min, then cooled to −78° C. A solution of6-bromo-2-methoxyquinoline (1.90 g, 7.964 mmol) in dry THF (15 mL) wasadded dropwise at −78° C. and the mixture was stirred at thistemperature for 75 min A solution of 48 (1.42 g, 7.964 mmol) in dry THF(6 mL) was added dropwise at −78° C., the reaction mixture remainedorange brown and was stirred at −78° C. for 2.5 hours. The mixture wasquenched with acetic acid (0.68 mL) at −65° C. Water was added, theaqueous mixture was extracted with EtOAc (2×), and the combined extractwas washed with brine, dried (MgSO₄) and concentrated in vacuo to givethe crude product as a yellow solid. Flash chromatography of the productusing 10-100% EtOAc in hexanes as eluent afforded the product 49 as anoff-white solid. Yield=1.90 g, 57%. ¹H NMR (CDCl₃) δ 8.15 (1H, d, J=2.4Hz), 8.01 (1H, s), 7.88 (1H, d, J=2.1 Hz), 7.69 (1H, d, J=8.9 Hz), 7.65(1H, dd, J=2.1, 9.0 Hz), 7.40 (1H, dd, J=2.5, 9.0 Hz), 6.42 (1H, d,J=8.9 Hz), 5.94 (1H, d, J=3.7 Hz), 4.04 (3H, s), 3.50 (4H, dq, J=1.7,7.1 Hz), 2.65 (1H, d, J=3.9 Hz), 1.17 (6H, t, J=7.0 Hz).

5-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-N,N-diethylpyridin-2-amine(50)

To a solution of 49 (1.90 g, 4.56 mmol) in freshly distilled THF (19 mL)was added at 2° C. under nitrogen sodium borohydride (0.86 g, 23.0 mmol)in 3 portions over 10 min. The mixture was stirred at 2-4° C. for 1hour. The mixture was cooled to 2° C. again and aluminium trichloride(1.83 g, 13.70 mmol) was added in 4 batches over 15 min. The mixture wasstirred at 2° C. for 10 min, then refluxed for 2 hours. The mixture wasthen quenched with water cautiously at 2° C., until gas evolutionceased. The white slurry was filtered through Celite. The milky whitefiltrate was diluted in water, and the organic phase was collected. Theaqueous phase was extracted with EtOAc (3×). The organic extract waswashed with brine, dried (MgSO₄) and concentrated in vacuo to furnishthe crude product as a brownish residue. Flash chromatography of thecrude product using 10% EtOAc in hexanes as eluent afforded the product50 as a white solid. Yield=1.39 g, 76%. ¹H NMR (CDCl₃) δ 8.06 (1H, d,J=2.1 Hz), 7.75 (1H, d, J=2.2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.60 (1H, dd,J=2.2, 8.8 Hz), 7.52 (1H, s), 7.27 (1H, dd, J=2.4, 8.7 Hz), 6.43 (1H,dd, J=0.3, 8.7 Hz), 4.09 (3H, s), 3.85 (2H, s), 3.50 (4H, q, 7.0 Hz),1.18 (6H, t, J=7.0 Hz). Found: [M+H]=400.8

2,3-Difluoroisonicotinic acid (51)

To a solution of n-BuLi (26.1 mL, 52.09 mmol) in THF (70 mL, dist. Na)at −78° C. was added consecutively N,N-diisopropylamine (7.30 mL, 52.09mmol) and 2,3-difluoropyridine (5.00 g, 43.41 mmol). The resultantmixture was stirred at −78° C. for 1 hour, and then poured on crusheddry ice (excess). The reaction was allowed to warm to r.t. for 1 hour,and after evaporation of excess dry ice and THF, the residue was takenup into water (100 mL) and washed with EtOAc (2×50 mL). The aqueouslayer was then acidified to pH 1 and extracted with EtOAc (2×100 mL).The combined organic extracts were dried and evaporated to afford theproduct 51. Yield=2.39 g, 35%. ¹H NMR (CDCl₃) δ 15.3-13.2 (1H, br s),8.14 (1H, dd, J=1.2, 5.0 Hz), 7.70 (1H, dd, J=4.8, 4.8 Hz). Found:[M−H]=158.5.

3-Fluoro-2-methoxyisonicotinic acid (52)

Sodium (0.79 g, 33.09 mmol) was added portion wise to MeOH (60 mL) over0.5 h. 51 (2.39 g, 15.04 mmol) was then added and the reaction refluxedfor 2 hours. The solution was cooled and the solvent evaporated. Theresidue was taken up into water (100 mL) and washed with EtOAc (2×50mL). The aqueous layer was then acidified to pH 1 and extracted withEtOAc (2×100 mL). The combined organic extracts were dried andevaporated to afford the product 52. Yield=2.23 g, 87%. ¹H NMR (DMSO-d₆)δ 14.6-12.8 (1H, br s), 8.05 (1H, d, J=5.2 Hz), 7.28 (1H, dd, J=4.7, 4.9Hz), 3.97 (3H, s). Found: [M−H]=170.5.

(3-Fluoro-2-methoxypyridin-4-yl)methanol (53)

Borane-dimethylsulfide complex (2.47 mL, 26.07 mmol) and trimethylborate (2.96 mL, 26.07 mmol) were added to a solution of 52 (13.03 mmol)in THF (80 mL, dist. Na) at 0° C., and the solution warmed to r.t. andstirred overnight. The mixture was then cooled to 0° C., and quenchedwith methanol (10 mL). The solvent was then evaporated and the residuewas partitioned between EtOAc and water. The organic layer was thendried and evaporated to afford the product 53. Yield=1.89 g, 92%. ¹H NMR(CDCl₃) δ 7.92 (1H, d, J=5.2 Hz), 7.02 (1H, dd, J=4.5, 5.1 Hz), 4.81(2H, s), 4.03 (3H, s). Found: [M+H]=158.5.

4-(Bromomethyl)-3-fluoro-2-methoxypyridine (54)

To a solution of 53 (1.89 g, 12.03 mmol) and triethylamine (2.52 mL,18.05 mmol) in DCM (30 mL, anhydrous) at r.t. was added mesyl chloride(1.12 mL, 14.44 mmol) dropwise. After 15 min, the reaction was dilutedwith DCM (20 mL) and the organic layer washed with sat. NaHCO₃, driedand evaporated. The residue was dissolved in acetone (60 mL, anhydrous),lithium bromide (excess) added, and the mixture heated at reflux for 30min. The solution was then cooled and the solvent evaporated, and theresidue partitioned between EtOAc and water. The aqueous layer wasextracted twice with EtOAc and the organic layer was dried andevaporated to give the product 54. Yield=2.20 g, 83% ¹H NMR (CDCl₃) δ7.90 (1H, d, J=5.2 Hz), 6.90 (1H, dd, J=4.8, 4.9 Hz), 4.43 (2H, s), 4.02(3H, s). Found: [M+H]=220.2

6-Bromo-3-((3-fluoro-2-methoxypyridin-4-yl)methyl)-2-methoxyquinoline(55)

A mixture of 1 (2.56 g, 9.09 mmol), 54 (2.20 g, 10.00 mmol) and cesiumcarbonate (5.92 g, 18.18 mmol) in toluene (45 mL, anhydrous) and DMF(22.5 mL, anhydrous) was purged with nitrogen. Pd(PPh₃)₄ (0.42 g, 0.363mmol) was then added, the mixture purged with nitrogen, then heated to80° C. under nitrogen for 4 hours. The reaction was partitioned betweenEtOAc and water and the organic fraction was dried and evaporated.Column chromatography (19:1 hexanes/EtOAc) gave the product 55.Yield=1.76 g, 51%. ¹H NMR (CDCl₃) δ 7.82 (1H, d, J=5.2 Hz), 7.79 (1H, d,J=2.1 Hz), 7.69 (1H, d, J=8.8 Hz), 7.64 (1H, dd, J=2.2, 8.9 Hz), 7.60(1H, s), 6.69 (1H, dd, J=4.8, 5.0 Hz), 4.07 (3H, s), 4.06 (2H, s), 4.03(3H, s). Found: [M+H]=377.2

(2,6-Dimethoxypyridin-3-yl)boronic acid (56)

To a solution of 2,6-dimethoxypyridine (10 g, 71.84 mmol) andN,N-diisopropylamine (0.50 mL, 3.59 mmol) in THF (200 mL, dist. Na) at−40° C. under nitrogen was added n-BuLi (43.10 mL, 86.21 mmol) dropwise.The resultant solution was stirred at −40° C. for 5 min, and then warmedto 0° C. and stirred at this temperature for a further 3 hours. Thesolution was then again cooled to −40° C., and triisopropylborate (24.87mL, 107.76 mmol) was added dropwise, and the mixture stirred at r.t. foranother 1 hour. Water (50 mL) was added and the solvent was removed invacuo. To the residue was added 1M NaOH (100 mL) and the aqueous layerwashed with EtOAc (2×100 mL). The aqueous layer was then acidified to pH3 and a solid precipitated. This solid was filtered and dried to affordthe product 56. Yield=8.10 g, 61%. ¹H NMR (DMSO-d₆) δ 7.87 (1H, d, J=7.9Hz), 6.36 (1H, d, J=7.9 Hz), 3.90 (3H, s), 3.87 (3H, s).

2,6-Dimethoxypyridin-3-ol (57)

To a solution of 56 (8.00 g, 43.49 mmol) in THF (150 mL, dist. Na) at 0°C. was added dropwise 32% peracetic acid in acetic acid (21.53 mL, 86.98mmol) over 10 min. The resultant solution was stirred at r.t. for 2 h. A10% solution of sodium sulfite (75 mL) was then added and the mixturestirred at r.t. for 0.5 hour. The solvent was evaporated and the residuepartitioned between EtOAc and water. The aqueous layer was extractedtwice and the organic layer dried and evaporated. Column chromatographywith 9:1 hexanes/EtOAc afforded the product 57. Yield=6.05 g, 90%. ¹HNMR (CDCl₃) δ 7.12 (1H, d, J=8.3 Hz), 6.21 (1H, d, J=8.2 Hz), 4.90 (1H,s), 7.00 (3H, s), 3.86 (3H, s). Found: [M+H]=156.7.

3-(Ethoxymethoxy)-2,6-dimethoxypyridine (58)

To a solution of 57 (6.45 g, 40.97 mmol) in DMF (70 mL, anhydrous) at 0°C. was added 60% sodium hydride in mineral oil (41.97 g, 9.16 mmol) inportions. The mixture was warmed to r.t. and stirred for 1 hour.1-Chloro-2-methoxyethane (4.37 mL, 47.11 mmol) was then added, and theresultant mixture stirred at r.t. for a further 2 hours. The reactionwas diluted with brine (100 mL) and extracted with EtOAc three times.The organic layer was washed with brine three times, dried andevaporated. Column chromatography with 19:1 hexanes/EtOAc afforded theproduct 58. Yield: 8.14 g, 93%. ¹H NMR (CDCl₃) δ 7.41-7.33 (1H, m),6.26-6.17 (1H, m), 5.15 (2H, d, J=1.9 Hz), 3.98 (3H, d, J=1.8 Hz), 3.87(3H, d, J=2.0 Hz), 3.77 (2H, dq, J=1.8, 7.1 Hz), 1.22 (3H, dt, J=2.9,7.0 Hz).

3-Hydroxy-2,6-dimethoxyisonicotinic acid (59)

To a solution of 58 (4.95 g, 23.24 mmol) and N,N-diisopropylamine (0.16mL, 1.16 mmol) in THF (80 mL, dist. Na) at −40° C. under nitrogen wasadded n-BuLi (17.43 mL, 34.86 mmol) dropwise. The resultant solution wasstirred at −40° C. for 5 min, and then warmed to 0° C. and stirred atthis temperature for a further 3 hours. The solution was then againcooled to −40° C., and dry ice (20 g, excess) was added, and the mixturestirred at r.t. for another 1 hour. Water (25 mL) was added and thesolvent was removed in vacuo. To the residue was added 1M NaOH (100 mL)and the aqueous layer washed with EtOAc (2×100 mL). The aqueous layerwas then acidified to pH 1 using conc. hydrochloric acid and a solidprecipitated. This solid was filtered and dried to afford the product59. Yield=3.85 g, 83%. ¹H NMR (DMSO-d₆) δ 6.52 (1H, s), 3.90 (3H, s),3.79 (3H, s). Found: [M+H]=200.5.

Methyl 2,3,6-trimethoxyisonicotinate (60)

A mixture of 59 (3.85 g, 19.34 mmol) and potassium carbonate (10.70 g,7.39 mmol) in DMF (100 mL, anhydrous) was heated at 50° C. for 15 min.Methyl iodide (3.61 mL, 58.03 mmol) was then added and the mixturestirred at this temperature for 2 hours. The resultant solution wasdiluted with EtOAc and washed with brine three times. The organic layerwas dried and evaporated. Column chromatography with 9:1 hexanes/EtOAcafforded the product 60. Yield=3.63 g, 96%. ¹H NMR (CDCl₃) δ 6.51 (1H,s), 4.01 (3H, s), 3.92 (3H, s), 3.89 (3H, s), 3.83 (3H, s).

2,3,6-Trimethoxyisonicotinic acid (61)

A solution of 60 (3.60 g, 55.86 mmol) in 1M NaOH (100 mL) was heated at50° C. for 2 hours. The reaction was cooled and washed with EtOAc (2×50mL). The aqueous layer was then acidified to pH 1 and the solid filteredand dried to afford the product 61. Yield=3.04 g, 90%. ¹H NMR (DMSO-d₆)δ 14.3-12.2 (1H, br s), 6.42 (1H, s), 3.93 (3H, s), 3.83 (3H, s), 3.69(3H, s). Found: [M+H]=214.5

N,2,3,6-Tetramethoxy-N-methylisonicotinamide (62)

Oxalyl chloride (1.46 mL, 16.90 mmol) was added to a solution of 61(3.00 g, 14.08 mmol) in DCM (60 mL, anhydrous) and DMF (0.22 mL, 2.82mmol) at r.t. The mixture was stirred at r.t. for 1 hour, and then thesolvent was evaporated and the residue washed with benzene (2×50 mL).The residue was redissolved in DMF (60 mL, anhydrous) and cooled to 0°C. N,O-dimethylhydroxylamine hydrochloride (1.51 g, 15.49 mmol) andpyridine (3.75 mL, 46.46 mmol) were added sequentially and the mixturewas stirred at r.t. for 2 hours, then partitioned between EtOAc and sat.aq. NaHCO₃. Column chromatography with 9:1 hexanes/EtOAc gave theproduct 62. Yield=2.89 g, 80%. ¹H NMR (CDCl₃) δ 6.18 (1H, s), 4.01 (3H,s), 3.89 (3H, s), 3.80 (3H, s), 3.60-3.47 (3H, br s), 3.42-3.26 (3H, s).Found: [M+H]=257.6.

3-(Dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)propan-1-one (63)

Vinylmagnesium bromide in THF (1N, 22.13 mL, 22.13 mmol) was added to asolution of 62 (2.70 g, 10.54 mmol) in THF (80 mL, dist. Na) at 0° C.,then the yellow/orange solution was warmed to r.t. for 1 hour.Dimethylamine in THF (2N, 22.13 mL, 44.27 mmol) then water (30 mL) wereadded. The solution was stirred at r.t. for 1 hour, the solvent removedin vacuo, and the resultant mixture then partitioned between EtOAc andwater. The solution was dried and evaporated to afford the product 63.Yield=2.81 g, 99%. ¹H NMR (CDCl₃) δ 6.32 (1H, s), 4.01 (3H, s), 3.89(3H, s), 3.81 (3H, s), 3.08 (2H, t, J=7.2 Hz), 2.68 (2H, t, J=7.2 Hz),2.24 (6H, s). Found: [M-Me₂N]=224.5.

(3-Fluoro-4-methoxyphenyl)methanol (64)

Borane-dimethylsulfide complex (2.79 mL, 29.40 mmol) and trimethylborate (3.34 mL, 29.40 mmol) were added to a solution of3-fluoro-4-methoxybenzoic acid (2.50 g, 14.69 mmol) in THF (80 mL, dist.Na) at 0° C., and the solution warmed to r.t. and stirred overnight. Themixture was then cooled to 0° C., and quenched with MeOH (10 mL). Thesolvent was then evaporated and the residue was partitioned betweenEtOAc and water. The organic layer was then dried and evaporated toafford the product 64. Yield=2.35 g, 100%. ¹H NMR (CDCl₃) δ 7.11 (1H,dd, J=2.0, 11.9 Hz), 7.06 (1H, ddd, J=0.9, 2.0, 9.1 Hz), 6.94 (1H, dd,J=8.4, 8.4 Hz), 4.61 (2H, s), 3.89 (3H, s), 1.73 (1H, s). Found:[M-OH]=139.7.

4-(Bromomethyl)-2-fluoro-1-methoxybenzene (65)

To a solution of 64 (2.35 g, 15.05 mmol) and triethylamine (3.15 mL,22.58 mmol) in DCM (50 mL, anhydrous) at r.t. was added mesyl chloride(1.41 mL, 18.06 mmol) dropwise. After 15 min, the reaction was dilutedwith DCM (50 mL) and the organic layer washed with sat. aq. NaHCO₃,dried and evaporated. The residue was dissolved in acetone (100 mL,anhydrous), lithium bromide (excess) added, and the mixture heated atreflux for 30 min. The solution was then cooled and the solventevaporated, and the residue partitioned between EtOAc and water. Theaqueous layer was extracted twice with EtOAc and the organic layer wasdried and evaporated to afford the product 65. Yield=3.00 g, 91%. ¹H NMR(CDCl₃) δ 7.16-7.07 (2H, m), 6.90 (1H, dd, J=8.3, 8.4 Hz), 4.45 (2H, s),3.89 (3H, s).

6-Bromo-3-(3-fluoro-4-methoxybenzyl)-2-methoxyquinoline (66)

A mixture of 1 (3.51 g, 12.45 mmol), 65 (3.00 g, 13.69 mmol) and cesiumcarbonate (8.93 g, 27.40 mmol) in toluene (60 mL, anhydrous) and DMF (30mL, anhydrous) was purged with nitrogen. Pd(PPh₃)₄ (0.58 g, 0.50 mmol)was then added, the mixture purged with nitrogen then heated to 80° C.under nitrogen for 5 hours. The reaction was partitioned between EtOAcand water and the organic fraction was dried and evaporated. Columnchromatography (19:1 hexanes/EtOAc) gave the product 66. Yield=2.10 g,41%. ¹H NMR (CDCl₃) δ 7.76 (1H, d, J=2.2 Hz), 7.69 (1H, d, J=12.3 Hz),7.62 (1H, dd, J=2.2, 8.9 Hz), 7.49 (1H, s), 7.00-6.86 (3H, m), 4.07 (3H,s), 3.95 (2H, s), 3.88 (3H, s). Found: [M+H]=376.0

3-(Ethoxymethoxy)-2,6-dimethoxyisonicotinaldehyde (67)

To a solution of 58 (4.00 g, 18.78 mmol) and N,N-diisopropylamine (0.13mL, 0.94 mmol) in THF (60 mL, dist. Na) at −40° C. under nitrogen wasadded n-BuLi (14.09 mL, 28.17 mmol) dropwise. The resultant solution wasstirred at −40° C. for 5 min, and then warmed to 0° C. and stirred atthis temperature for a further 3 hours. The solution was then againcooled to −40° C., and 1-formylpiperidine (3.75 mL, 33.80 mmol) wasadded dropwise, and the mixture stirred at r.t. for another 1 hour.Acetic acid (7.5 mL) was added and the solvent was removed in vacuo. Theresultant mixture was partitioned between EtOAc and water, and theorganic fraction dried and evaporated. Column chromatography with 19:1hexanes/EtOAc afforded the product 67. Yield=2.30 g, 51%. ¹H NMR (CDCl₃)δ 10.39 (1H, s), 6.61 (1H, s), 6.19 (2H, s), 4.02 (3H, s), 3.88 (3H, s),3.78 (2H, q, J=10.1 Hz), 1.21 (3H, t, J=7.1 Hz).

3-Hydroxy-2,6-dimethoxyisonicotinaldehyde (68)

A solution of 67 (2.30 g, 9.54 mmol) and 3M hydrochloric acid (60 mL) inTHF (30 mL, dist. Na) was heated at 40° C. for 1.5 hours. The solutionwas then cooled, diluted with water, and the pH adjusted to 7 usingNaHCO₃. The aqueous layer was then extracted with EtOAc three times, andthe organic layer dried and evaporated. Column chromatography with 19:1hexanes/EtOAc afforded the product 68. Yield=1.36 g, 78%. ¹H NMR (CDCl₃)δ 9.96 (1H, s), 9.61 (1H, s), 6.46 (1H, s), 4.06 (3H, s), 3.91 (3H, s).

2,3,6-Trimethoxyisonicotinaldehyde (69)

A mixture of 68 (1.35 g, 7.38 mmol) and potassium carbonate (1.53 g,11.07 mmol) in DMF (40 mL, anhydrous) was heated at 50° C. for 10 min.Methyl iodide (0.56 mL, 8.86 mmol) was then added and the mixturestirred at this temperature for 2 hours. The resultant solution wasdiluted with EtOAc and washed with brine three times. The organic layerwas dried and evaporated to afford the product 69. Yield=1.40 g, 96%. ¹HNMR (CDCl₃) δ 10.40 (1H, s), 6.58 (1H, s), 4.04 (3H, s), 3.93 (3H, s),3.91 (3H, s).

(2,3,6-Trimethoxypyridin-4-yl)methanol (70)

A mixture of 69 (1.40 g, 7.11 mmol) and sodium borohydride (0.54 g,14.21 mmol) in MeOH (30 mL, anhydrous) was stirred at r.t. for 1 hour.The solvent was then removed and the residue partitioned between EtOAcand water. The organic layer was dried and evaporated to afford theproduct 70. Yield=1.35 g, 95%. ¹H NMR (CDCl₃) δ 6.30 (1H, s), 4.68 (2H,d, J=5.6 Hz), 3.99 (3H, s), 3.88 (3H, s), 3.79 (3H, s), 2.21 (1H, t,J=5.9 Hz).

4-(Bromomethyl)-2,3,6-trimethoxypyridine (71)

To a solution of 70 (1.35 g, 6.78 mmol) and triethylamine (1.42 mL,10.78 mmol) in DCM (20 mL, anhydrous) at r.t. was added mesyl chloride(0.63 mL, 8.14 mmol) dropwise. After 15 min, the reaction was dilutedwith DCM (20 mL) and the organic layer washed with sat. aq. NaHCO₃,dried and evaporated. The residue was dissolved in acetone (40 mL,anhydrous), lithium bromide (excess) added, and the mixture heated atreflux for 30 min. The solution was then cooled and the solventevaporated, and the residue partitioned between EtOAc and water. Theaqueous layer was extracted twice with EtOAc and the organic layer wasdried and evaporated to give the product 71. Yield=1.69 g, 95%. ¹H NMR(CDCl₃) δ 6.27 (1H, s), 4.40 (2H, s), 3.98 (3H, s), 3.87 (3H, s), 3.87(3H, s). Found: [M+H]=262.5

6-Bromo-2-methoxy-3-((2,3,6-trimethoxypyridin-4-yl)methyl)quinolone (72)

A mixture of 1 (1.89 g, 6.69 mmol), 71 (1.67 g, 6.37 mmol) and cesiumcarbonate (4.15 g, 12.74 mmol) in toluene (40 mL, anhydrous) and DMF (20mL, anhydrous) was purged with nitrogen. Pd(PPh₃)₄ (0.29 g, 0.26 mmol)was then added, the mixture purged with nitrogen then heated to 80° C.under nitrogen for 4 hours. The reaction was partitioned between EtOAcand water and the organic fraction was dried and evaporated. Columnchromatography (19:1 hexanes/EtOAc) gave the product 72. Yield=1.44 g,54%. ¹H NMR (CDCl₃) δ 7.76 (1H, d, J=2.2 Hz), 7.68 (1H, d, J=8.9 Hz),7.61 (1H, dd, J=2.2, 8.8 Hz), 7.54 (1H, s), 6.04 (1H, s), 4.07 (3H, s),4.00 (3H, s), 4.39 (2H, s), 3.85 (3H, s), 3.72 (3H, s). Found:[M+H]=420.0

Methyl 2-(dimethylamino)-6-(ethylthio)isonicotinate (73)

To a glass tube was charged methyl2-chloro-6-(dimethylamino)isonicotinate (WO 2010/100475) (2.44 g, 11.40mmol), rac-bis(diphenylphosphino)-1,1′-binaphthol (0.71 g, 1.140 mmol)and cesium carbonate (4.43 g, 13.60 mmol) under continuous nitrogenflow. Anhydrous toluene (30 mL) was added. The mixture was purged withnitrogen for 5 min Palladium acetate (0.26 g, 1.158 mmol) was added andthe mixture was purged again with nitrogen. Ethanethiol (1.0 mL, 13.60mmol) was added and the mixture was sealed in the tube and heated at150° C. for 22 hours. The mixture was filtered through Celite, washingwith EtOAc. The filtrate was concentrated in the fume hood by heatingthe solution while purging with air. A crude orange solid was obtained.Flash chromatography of the product using 2-5% diethyl ether in hexanesprovided the product 73 as a yellow crystalline solid. Yield=2.42 g,88%. %. ¹H NMR (CDCl₃) δ 6.96 (1H, d, J=1.0 Hz), 6.73 (1H, d, J=1.0 Hz),3.89 (3H, s), 3.15 (2H, q, 7.3 Hz), 3.12 (6H, s), 1.38 (3H, t, J=7.3Hz). Found: [M+H]=241.5.

(2-(Dimethylamino)-6-(ethylthio)pyridin-4-yl)methanol (74)

To a solution of 73 (1.64 g, 6.824 mmol) in freshly distilled THF (66mL) was added at 2° C. under nitrogen lithium aluminium hydride (0.31 g,8.189 mmol) in 3 batches. The mixture was stirred at 2° C. for 15 minthen at r.t. for 1 hour. The mixture was quenched cautiously with waterat 2° C. until gas evolution ceased. 1M NaOH (20 mL) was added. Themixture was stirred for 5 min, then decanted leaving the aluminium saltswhich were filtered through Celite. The aqueous mixture was partitionedbetween water and EtOAc. The aqueous phase was extracted with EtOAc(3×). The combined organic extract was washed with brine, dried (Na₂SO₄)and concentrated to give the crude product as a brown oil. The crudeproduct was purified by flash chromatography using a 4:1 mixture ofhexanes/EtOAc to afford the product 74 as a brown oil. Yield=1.30 g,90%. ¹H NMR (CDCl₃) δ 6.43 (1H, s), 6.18 (1H, d, J=0.8 Hz), 4.56 (2H, d,J=5.0 Hz), 3.14 (2H, q, 7.4 Hz), 3.08 (6H, s), 1.67 (1H, br t, J=5.8Hz), 1.57 (3, s), 1.37 (3H, t, J=7.3 Hz). Found: [M+H]=213.5.

4-(Bromomethyl)-6-(ethylthio)-N,N-dimethylpyridin-2-amine (75)

To a solution of 74 (0.60 g, 2.84 mmol) in anhydrous DCM (10 mL) wasadded at 2° C. under nitrogen triethylamine (0.59 mL, 4.26 mmol)dropwise, followed by mesyl chloride (0.26 mL, 3.41 mmol). The mixturewas stirred from 2° C. to 5° C. over 1 hour. The mixture was quenchedwith sat. aq. NaHCO₃ solution. The aqueous mixture was extracted withDCM (3×). The combined extract was washed with brine, dried (MgSO₄) andconcentrated to afford the crude product as a light brown oil. The crudeintermediate was dissolved in acetone (20 mL). Lithium bromide (0.99 g,11.36 mmol) was added and the suspension was stirred at r.t. for 2.5hours. Flash chromatography using 98:2 hexanes/Et₂O furnished theproduct 75 as a brown solid. The reaction was repeated on a 3.29 mmolscale and the products were combined. Total yield=1.39 g, 82%. ¹H NMR(CDCl₃) δ 6.46 (1H, d, J=1.2 Hz), 6.15 (1H, d, J=0.8 Hz), 4.24 (2H, s),3.13 (2H, q, J=7.2 Hz), 3.08 (6H, s), 1.37 (3H, t, J=7.2 Hz). Found:[M+H]=275.5

4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-(ethylthio)-N,N-dimethylpyridin-2-amine(76)

A mixture of 1 (1.42 g, 5.05 mmol), 75 (1.39 g, 5.05 mmol) and cesiumcarbonate (3.29 g, 10.09 mmol) in a mixture of toluene (14 mL) and DMF(7 mL) was purged with nitrogen. Pd(PPh₃)₄ (0.29 g) was added. Themixture was purged again with nitrogen and heated at 85° C. undernitrogen for 2.5 hours. The mixture was partitioned between water andEtOAc. The aqueous mixture was extracted with EtOAc (2×). The extractwas washed with water, brine, dried (MgSO4) and concentrated to affordthe crude product as an orange oil which was chromatographed using 2-5%Et₂O in hexanes as eluent to yield the product 76 as a light yellowsolid. Recrystallisation from DCM/MeOH provided a white solid.Yield=1.25 g, 57%. ¹H NMR (CDCl₃) δ 7.79 (1H, d, J=2.4 Hz), 7.70 (1H, d,J=8.8 Hz), 7.64 (1H, dd, J=2.4, 9.2 Hz), 7.56 (1H, s), 6.34 (1H, s),6.06 (1H, s), 4.09 (3H, s), 3.86 (2H, s), 6.15 (2H, q, J=7.2 Hz), 3.07(6H, s), 1.39 (3H, t, J=7.2 Hz). Found [M+H]=432.1

2,5-Dimethoxynicotinaldehyde (77)

A mixture of 5-hydroxy-2-methoxynicotinaldehyde (Organic & BiomolecularChemistry, 6(8), 1364-1376; 2008) (3.20 g, 20.89 mmol) and potassiumcarbonate (4.33 g, 31.34 mmol) in DMF (100 mL, anhydrous) was heated at50° C. for 10 min. Methyl iodide (1.56 mL, 25.08 mmol) was then addedand the mixture stirred at this temperature for 2 hours. The resultantsolution was diluted with EtOAc and washed with brine three times. Theorganic layer was dried and evaporated to afford the product 77,identical to the compound reported in Organic & Biomolecular Chemistry,6(8), 1364-1376; 2008. Yield=2.70 g, 77%.

(2,5-Dimethoxypyridin-3-yl)methanol (78)

A mixture of 77 (2.70 g, 16.15 mmol) and sodium borohydride (1.22 g,32.30 mmol) in methanol (60 mL, anhydrous) was stirred at r.t. for 1 h.The solvent was then removed and the residue partitioned between EtOAcand water. The organic layer was dried and evaporated to afford theproduct 78. Yield: 2.74 g, 99%. ¹H NMR (CDCl₃) δ 7.72 (1H, d, J=3.0 Hz),7.26 (1H, d, J=3.0 Hz), 4.62 (2H, d, J=6.3 Hz), 3.94 (3H, s), 3.81 (3H,s), 2.37 (1H, t, J=6.4 Hz).

3-(Bromomethyl)-2,5-dimethoxypyridine (79)

To a solution of 78 (2.65 g, 15.66 mmol) and triethylamine (3.27 mL,23.49 mmol) in DCM (45 mL, anhydrous) at r.t. was added mesyl chloride(13.46 mL, 18.79 mmol) dropwise. After 15 min, the reaction was dilutedwith DCM (25 mL) and the organic layer washed with sat. NaHCO₃, driedand evaporated. The residue was dissolved in acetone (90 mL, anhydrous),lithium bromide (excess) was added, and the mixture heated at reflux for30 min. The solution was then cooled and the solvent evaporated, and theresidue partitioned between EtOAc and water. The aqueous layer wasextracted twice with EtOAc and the organic layer was dried andevaporated to afford the product 79. Yield=3.08 g, 85%. ¹H NMR (CDCl₃) δ7.78 (1H, d, J=3.0 Hz), 7.25 (1H, d, J=3.6 Hz), 4.46 (2H, s), 3.97 (3H,s), 3.82 (3H, s).

6-Bromo-3-((2,5-dimethoxypyridin-3-yl)methyl)-2-methoxyquinoline (80)

A mixture of 1 (3.40 g, 12.06 mmol), 79 (3.08 g, 13.27 mmol) and cesiumcarbonate (7.86 g, 24.12 mmol) in toluene (60 mL, anhydrous) and DMF (30mL, anhydrous) was purged with nitrogen. Pd(PPh₃)₄ (0.057 g, 0.48 mmol)was then added, the mixture purged with nitrogen then heated to 80° C.under nitrogen for 4 hours. The reaction was partitioned between EtOAcand water and the organic fraction was dried and evaporated. Columnchromatography (19:1 hexanes/EtOAc) gave the product 80. Yield=3.60 g,69%. ¹H NMR (CDCl₃) δ 7.77 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=3.0 Hz),7.68 (1H, d, J=8.9 Hz), 7.61 (1H, dd, J=2.2, 8.9 Hz), 7.55 (1H, s), 7.04(1H, d, J=3.0 Hz), 4.07 (3H, s), 3.94 (2H, s), 3.90 (3H, s), 3.78 (3H,s). Found: [M+H]=389.8

2,6-Dimethoxy-3-((triisopropylsilyl)oxy)pyridine (81)

To a mixture of 57 (8.05 g, 51.9 mmol) and imidazole (7.42 g, 108.99mmol) in DMF (130 mL) at r.t. was added triisopropylsilyl chloride(13.33 mL, 62.23 mmol), and the resultant mixture stirred at r.t. for 2hours. The solution was then partitioned between EtOAc and water, andthe aqueous layer extracted three times. The combined organic layerswere washed with brine three times, dried and evaporated. Columnchromatography with 19:1 hexanes/EtOAc afforded the product 81. Yield:15.59 g, 96%. ¹H NMR (CDCl₃) δ 7.07 (1H, d, J=8.2 Hz), 6.13 (1H, d,J=8.2 Hz), 3.92 (3H, s), 3.86 (3H, s), 1.27-1.18 (3H, m), 1.08 (18H, d,J=7.1 Hz). Found: [M+H]=312.8.

2,6-Dimethoxy-5-((triisopropylsilyl)oxy)nicotinaldehyde (82)

To a solution of 81 (8.00 g, 25.69 mmol) and N,N-diisopropylamine (0.18mL, 1.28 mmol) in THF (100 mL, dist. Na) at −40° C. under nitrogen wasadded n-BuLi (15.41 mL, 30.83 mmol) dropwise. The resultant solution wasstirred at −40° C. for 5 min, and then warmed to 0° C. and stirred atthis temperature for a further 3 hours. The solution was then againcooled to −40° C., and formylpiperidine (4.28 mL, 38.54 mmol) was addeddropwise, and the mixture stirred at r.t. for another 1 hour. Aceticacid (8 mL) was added and the solvent was removed in vacuo. Theresultant mixture was partitioned between EtOAc and water, and theorganic fraction dried and evaporated. Column chromatography with 49:1hexanes/EtOAc afforded the product 82. Yield=7.55 g, 87%. ¹H NMR (CDCl₃)δ 10.17 (1H, s), 7.51 (1H, s), 4.02 (3H, s), 4.01 (3H, s), 1.30-1.19(3H, m), 1.08 (18H, d, J=7.3 Hz). Found: [M-CHO]⁺=312.8.

5-Hydroxy-2,6-dimethoxynicotinaldehyde (83)

Tetrabutylammonium fluoride in THF (1N, 33.36 mL, 33.36 mmol) was addedto a solution of 82 (7.55 g, 22.24 mmol) in THF (35 mL, dist. Na) at 0°C. The reaction was then warmed to r.t. and stirred for 4 hours. Thesolvent was removed and the residue partitioned between EtOAc and water.The aqueous layer was extracted with EtOAc three times, and the organiclayer dried and evaporated. Column chromatography with DCM followed by3:1 DCM/EtOAc afforded the product 83. Yield=3.15 g, 77%. ¹H NMR (CDCl₃)δ 10.20 (1H, s), 7.59 (1H, s), 5.15-4.80 (1H, br s), 4.10 (3H, s), 4.01(3H, s).

2,5,6-Trimethoxynicotinaldehyde (84)

A mixture of 83 (3.15 g, 17.20 mmol) and potassium carbonate (3.57 g,25.80 mmol) in DMF (80 mL, anhydrous) was heated at 50° C. for 10 min.Methyl iodide (1.29 mL, 20.64 mmol) was then added and the mixturestirred at this temperature for 2 hours. The resultant solution wasdiluted with EtOAc and washed with brine three times. The organic layerwas dried and evaporated to afford the product 84. Yield=3.39 g, 100%.¹H NMR (CDCl₃) δ 10.21 (1H, s), 7.53 (1H, s), 4.10 (3H, s), 4.02 (3H,s), 3.87 (3H, s).

(6-Bromo-2-methoxyquinolin-3-yl)(2,5,6-trimethoxypyridin-3-yl)methanol(85)

A solution of 2,2,6,6-tetramethylpiperidine (3.59 mL, 21.03 mmol) in THF(40 mL, dist. Na) was cooled to −40° C., n-BuLi (10.52 mL, 21.03 mmol)was added and the solution was stirred at −40° C. for 15 min, thencooled to −78° C. A solution of 6-bromo-2-methoxyquinoline (17.53 mmol)in THF (40 mL, dist. Na) was added dropwise, the orange solution wasstirred at −78° C. for 1.5 hours, then a solution of 84 (3.42 g, 17.53mmol) in THF (40 mL, dist. Na) was added. The mixture was stirred at−78° C. for 2 hours, then acetic acid (2.5 mL) was added and thesolution was allowed to warm to r.t. The solvent was removed and theresidue partitioned between EtOAc and water, and the organic fractionwas dried and evaporated. Column chromatography with 9:1 hexanes/EtOAcfollowed by 4:1 hexanes/EtOAc gave the product as a white solid.Yield=5.50 g, 72%. ¹H NMR (CDCl₃) δ 7.85 (1H, d, J=2.1 Hz), 7.79 (1H,s), 7.70 (1H, d, J=8.9 Hz), 7.65 (1H, dd, J=2.1, 8.9 Hz), 7.15 (1H, s),6.14 (1H, d, J=5.2 Hz), 4.08 (3H, s), 4.02 (3H, s), 3.90 (3H, s), 3.78(3H, s), 3.48 (1H, d, J=5.4 Hz). Found: [M+H]=436.1

6-Bromo-2-methoxy-3-((2,5,6-trimethoxypyridin-3-yl)methyl)quinolone (86)

Trifluoroacetic acid (11.30 mL, 148.2 mmol) and triethylsilane (17.76mL, 111.2 mmol) were added sequentially to a solution of 85 (5.35 g,12.35 mmol) in DCM (125 mL) and the solution was stirred for 1 hour atr.t., then ice water was added. The solution was partitioned betweensat. aq. NaHCO₃ and DCM and the aqueous fraction was extracted with DCM.The organic fractions were combined, dried and evaporated. Columnchromatography with 9:1 hexanes/EtOAc gave the product 86 as a whitesolid. Yield=4.45 g, 86%. ¹H NMR (CDCl₃) δ 7.76 (1H, d, J=2.2 Hz), 7.68(1H, d, J=8.9 Hz), 7.60 (1H, dd, J=2.2, 8.4 Hz), 7.49 (1H, s), 7.05 (1H,s), 4.09 (3H, s), 4.01 (3H, s), 3.89 (5H, s), 3.79 (3H, s). Found:[M+H]=419.0

Ethyl 2-(dimethylamino)-6-methoxyisonicotinate (87)

To a glass tube was charged ethyl 2-chloro-6-methoxyisonicotinate (WO2009/024905) (4.01 g, 18.60 mmol), diphenylphosphino-1,1′-binaphthol(1.85 g, 2.976 mmol) and cesium carbonate (8.49 g, 26.10 mmol) undercontinuous nitrogen flow. Anhydrous toluene (72 mL) was added. Themixture was purged with nitrogen for 5 min. Palladium acetate (0.33 g,1.488 mmol) was added, the mixture was purged again with nitrogen.Dimethylamine in tetrahydrofuran (2N, 11.2 mL, 22.3 mmol) was added andthe mixture was sealed in the tube and heated at 80° C. for 19.5 hours.The mixture was filtered through Celite, washing with EtOAc. Thefiltrate was concentrated in vacuo to yield the crude product as a darkred liquid. Flash column chromatography of the crude product using 3-10%Et₂O in hexanes provided the product 87 as a yellow crystalline solid.Yield=3.36 g, 80%. ¹H NMR (CDCl₃) δ 6.61 (1H, d, J=0.96 Hz), 6.52 (1H,d, J=0.88 Hz), 4.35 (2H, q, J=7.1 Hz), 3.90 (3H, s), 3.1 (6H, s), 1.38(3H, t, J=7.2 Hz). Found: [M+H]=225.5.

(2-(Dimethylamino)-6-methoxypyridin-4-yl)methanol (88)

To a solution of 87 (3.31 g, 14.8 mmol) in freshly distilled THF (70 mL)was added at 2° C. under nitrogen lithium aluminium hydride (0.73 g,19.3 mmol) in 3 batches. The mixture was stirred at 2° C. for 10 minthen at r.t. for 1 hour. The mixture was quenched cautiously with waterat 2° C. until gas evolution ceased. 1M NaOH (30 mL) was added and themixture was stirred for 1 hour, then the aqueous mixture was diluted inwater and extracted with EtOAc (3×). The combined organic extract waswashed with brine, dried (Na₂SO₄) and concentrated to give the product88 as a light-yellow oil, which was used without further purification.Yield=2.69 g, >99%. ¹H NMR (CDCl₃) δ 6.05 (1H, d, J=0.4 Hz), 5.97 (1H,d, J=0.4 Hz), 4.59 (2H, d, J=4.8 Hz), 3.88 (3H, s), 3.06 (6H, s), 1.70(1H, t, J=5.6 Hz).

4-(Bromomethyl)-6-methoxy-N,N-dimethylpyridin-2-amine (89)

To a solution of 88 (3.30 g, 18.1 mmol) in anhydrous DCM (54 mL) wasadded at 2° C. under nitrogen triethylamine (3.8 mL, 27.2 mmol)dropwise, followed by mesyl chloride (1.7 mL, 21.7 mmol). The mixturewas stirred from 2° C. for 10 min, then at r.t. for 2 hours. The mixturewas quenched with sat. aq. NaHCO₃ solution. The aqueous mixture wasextracted with DCM (2×) and the combined extract was washed with brine,dried (MgSO₄) and concentrated to afford the crude product as a beigesolid. The crude intermediate was dissolved in acetone (60 mL). Lithiumbromide (1.53 g, 36.2 mmol) was added and the suspension was refluxedfor 2 hours. Flash chromatography using a mixture of 3-5% Et₂O inhexanes as eluent gave the product 89 as a mobile yellow oil. Yield=3.78g, 85%. ¹H NMR (CDCl₃) δ 6.02 (1H, d, J=0.8 Hz), 6.00 (1H, d, J=0.4 Hz),4.27 (2H, s), 3.88 (3H, s), 3.06 (6H, s).

4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-methoxy-N,N-dimethylpyridin-2-amine(90)

A mixture of 1 (4.34 g, 15.4 mmol), 89 (3.77 g, 115.4 mmol) and cesiumcarbonate (10.03 g, 30.8 mmol) in a mixture of toluene (40 mL) and DMF(20 mL) was purged with nitrogen. Pd(PPh₃)₄ (0.890 g, 0.774 mmol) wasadded and the mixture was purged again with nitrogen and heated at 85°C. under nitrogen for 3.5 hours. The mixture was partitioned betweenwater and EtOAc and the mixture was extracted with EtOAc (2×). Theextract was washed with water (2×), brine, dried (MgSO₄) andconcentrated to afford the crude product as a brown solid which waschromatographed using 3-10% Et₂O in hexanes as eluent to yield theproduct 90 as a light yellow solid. Yield=3.69 g, 60%. ¹H NMR (CDCl₃) δ7.76 (1H, d, J=2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.61 (1H, dd, J=2, 8.8Hz), 7.55 (1H, s), 5.92 (1H, s), 5.86 (1H, s), 4.07 (3H, s), 3.87 (5H,s), 3.04 (6H, s). Found: [M+H]=402.0

2-(Dimethylamino)-6-methoxyisonicotinic acid (91)

To a solution of 87 (6.77 g, 30.2 mmol) in EtOH (150 mL) was added atr.t. NaOH (30.2 mL, 60.4 mmol). The mixture was stirred at r.t. for 2hours and then concentrated in vacuo to a light yellow solution, whichwas further diluted in water. The aqueous mixture was acidified to pH˜2with 2M HCl, when bright yellow solids precipitated out. These werecollected by filtration, washed with water and dried under ambientconditions to yield 91 as a bright yellow powder. Yield=5.60 g, 95%. ¹HNMR (DMSO-d₆) δ 13.25 (1H, br s), 6.54 (1H, d, J=0.9 Hz), 6.33 (1H, d,J=0.8 Hz), 3.82 (3H, s), 3.04 (6H, s).

2-(Dimethylamino)-N,6-dimethoxy-N-methylisonicotinamide (92)

To a suspension of 91 (0.75 g, 3.81 mmol) in anhydrous DMF (22 mL) wasadded triethylamine (1.6 mL, 11.4 mmol), the mixture was cooled to 2° C.Ethyl chloroformate (0.62 mL, 4.19 mmol) was added dropwise and fumeswere evolved. The mixture was stirred from 2° C. to r.t. for 2.5 hoursand then treated with N,O-dimethylhydroxylamine hydrochloride (0.557 g,5.71 mmol) at 2° C. under nitrogen. The mixture was stirred to r.t.overnight. The mixture was diluted in water, and the aqueous mixture wasextracted with EtOAc (4×) and the organic extract was washed with water,brine, dried (MgSO₄) and concentrated to afford the crude product. Thiswas purified by repeated flash chromatography eluting with mixtures of4:1 then 2:1 hexanes/EtOAc as eluent, yielding the product 92 as ayellow oil. Yield=0.70 g, 77%. ¹H NMR (CDCl₃) δ 6.17 (1H, s), 6.11 (1H,s), 3.89 (3H, s), 3.62 (3H, br s), 3.31 (3H, s), 3.08 (6H, s).

3-(Dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)propan-1-one(93)

To a solution of 92 (2.53 g, 10.60 mmol) in freshly distilled THF (96mL) was added at 2° C. under nitrogen vinylmagnesium bromide in THF (1N,21.1 mL, 21.10 mmol) dropwise. The mixture was stirred at 2° C. for 20min, then at r.t. for 75 min. Dimethylamine in THF (2N, 21.1 mL, 42.20mmol) was added, followed by water (40 mL). The mixture was stirred atr.t. for 1 hour. The aqueous mixture was partitioned between water andEtOAc and the organic phase was separated and the aqueous phase wasextracted with EtOAc (2×). The organic extract was washed with brine,dried (Na₂SO₄) and concentrated in vacuo to give the crude product as ayellow-brown oil. Flash chromatography of the product using 2-8% MeOH inDCM as eluent gave 93 as a yellow oil which crystallised at −20° C.Yield=1.91 g, 72%. ¹H NMR (CDCl₃) δ 6.47 (1H, d, J=1.0 Hz), 6.39 (1H, d,J=1.0 Hz), 3.91 (3H, s), 3.10 (6H, s), 3.06 (2H, t, J=7.0 Hz), 2.72 (2H,t, J=7.1 Hz), 2.27 (6H, s).

Ethyl 2-(dimethylamino)-6-ethoxyisonicotinate (94)

To a glass tube was charged ethyl 2-chloro-6-ethoxyisonicotinate (WO2010/080864) (1.00 g, 4.37 mmol), diphenylphosphino-1,1′-binaphthol(0.44 g, 0.70 mmol) and cesium carbonate (1.99 g, 6.12 mmol) undercontinuous nitrogen flow. Anhydrous toluene (24 mL) was added. Themixture was purged with nitrogen 5 min. Palladium acetate (0.079 g, 0.35mmol) was added, the mixture was purged again with nitrogen.Dimethylamine in THF (2N, 2.6 mL, 5.246 mmol) was added and the mixturewas sealed in the tube and heated at 80° C. overnight. The mixture wasfiltered through Celite, washing with EtOAc and the filtrate wasconcentrated in vacuo to yield the crude product as a dark red liquid.Flash chromatography using 2-4% Et₂O in hexanes gave the product 94 as alight yellow oil. Yield=0.85 g, 82%. ¹H NMR (CDCl₃) δ 6.60 (1H, d, J=0.8Hz), 6.51 (1H, d, J=0.8 Hz), 4.35 (2H, q, J=7.0 Hz), 4.33 (2H, q, J=7.1Hz), 3.09 (6H, s), 1.38 (3H, t, J=7.2 Hz), 1.37 (3H, t, J=7.2 Hz).

4-(Bromomethyl)-6-ethoxy-N,N-dimethylpyridin-2-amine (95)

To a solution of 94 (4.40 g, 18.50 mmol) in freshly distilled THF (90mL) was added at −78° C. under nitrogen lithium aluminium hydride (0.91g, 24.0 mmol) in 3 batches. The mixture was stirred at −78° C. for 15min then at r.t. for 1 hour. The mixture was quenched cautiously withwater at 2° C. until gas evolution ceased. 1M NaOH (32 mL) was added andthe mixture was stirred for 1 hour, then the aqueous mixture was dilutedwith water and extracted with EtOAc (3×). The combined organic extractwas washed with brine, dried (Na₂SO₄) and concentrated to give theproduct, which was purified via flash chromatography eluting withmixtures of 6:1 then 4:1 hexanes/EtOAc to give the alcohol intermediateas a light yellow oil. Yield=3.27 g, 90%. The material was used directlyin the next step without further characterisation.

To a solution of the alcohol intermediate (3.27 g, 16.7 mmol) inanhydrous DCM (50 mL) was added at 2° C. under nitrogen triethylamine(3.5 mL, 25.0 mmol) dropwise, followed by mesyl chloride (1.6 mL, 20.0mmol). The mixture was stirred from 2° C. for 10 min, then at r.t. for0.5 hour. The mixture was quenched with sat. aq. NaHCO₃ solution. Theaqueous mixture was extracted with DCM (3×) and the combined extract waswashed with brine, dried and concentrated to afford the crude product asa brown oil. This was diluted in acetone (60 mL), lithium bromide (1.42g) was added. And the suspension was refluxed for 2 hours. Flashchromatography using a mixture of 2-3% Et₂O in hexanes as eluent gavethe product 95 as a mobile yellow oil. Yield=3.84 g, 89%. ¹H NMR (CDCl₃)δ 6.011 (1H, s), 5.99 (1H, s), 4.30 (2H, q, J=6.8 Hz), 4.27 (2H, s),3.05 (6H, s), 1.37 (3H, t, J=7.2 Hz).

4-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-6-ethoxy-N,N-dimethylpyridin-2-amine(96)

A mixture of 1 (4.13 g, 14.7 mmol), 95 (3.80 g, 14.7 mmol) and cesiumcarbonate (9.58 g, 29.4 mmol) in a mixture of toluene (40 mL) and DMF(20 mL) was purged with nitrogen. Pd(PPh₃)₄ (0.68 g) was added. Themixture was purged again with nitrogen and heated at 85° C. undernitrogen for 3 hours. The mixture was partitioned between water andEtOAc and the aqueous mixture was extracted with EtOAc (2×). The extractwas washed with water (2×), brine, dried and concentrated to afford thecrude product as a brown oil. This was chromatographed using 3-10% Et₂Oin hexanes as eluent to yield the product 96 as a yellow solid (3.83 g),which was triturated in diethyl ether to afford the clean product as apale yellow solid. Yield=3.51 g, 57%. ¹H NMR (CDCl₃) δ 7.76 (1H, d,J=2.2 Hz), 7.68 (1H, d, J=8.8 Hz), 7.61 (1H, dd, J=2.2, 8.8 Hz), 7.55(1H, s), 5.91 (1H, s), 5.84 (1H, s), 4.30 (2H, q, J=7.1 Hz), 4.07 (3H,s), 3.87 (2H, s), 3.03 (6H, s), 1.36 (3H, t, J=7.1 Hz).

5-Isopropoxy-2-methoxynicotinaldehyde (97)

A mixture of 5-hydroxy-2-methoxynicotinaldehyde (Organic & BiomolecularChemistry, 6(8), 1364-1376; 2008) (1.00 g, 6.53 mmol) and potassiumcarbonate (1.35 g, 9.80 mmol) in DMF (30 mL, anhydrous) was heated at50° C. for 10 min Isopropyl iodide (0.78 mL, 7.84 mmol) was then addedand the mixture stirred at this temperature for 2 hours. The resultantsolution was diluted with EtOAc and washed with brine three times. Theorganic layer was dried and evaporated to afford the product 97.Yield=0.90 g, 71%. ¹H NMR (CDCl₃) δ 10.34 (1H, s), 8.07 (1H, d, J=3.2Hz), 7.66 (1H, d, J=3.2 Hz), 4.48 (1H, sp, J=6.1 Hz), 4.03 (3H, s), 1.33(6H, d, J=4.8 Hz).

(5-Isopropoxy-2-methoxypyridin-3-yl)methanol (98)

A mixture of 97 (0.90 g, 4.61 mmol) and sodium borohydride (0.35 g, 9.22mmol) in MeOH (15 mL, anhydrous) was stirred at r.t. for 1 hour. Thesolvent was then removed and the residue partitioned between EtOAc andwater. The organic layer was dried and evaporated. Column chromatographywith 9:1 hexanes/EtOAc afforded the product 98. Yield=0.68 g, 75%. ¹HNMR (CDCl₃) δ 7.72 (1H, s), 7.25 (1H, d, J=3 Hz), 4.61 (2H, s), 4.42(1H, sp), 3.93 (3H, s), 2.92-2.19 (1H, br s), 1.32 (6H, d, J=6.1 Hz).

3-(Bromomethyl)-5-isopropoxy-2-methoxypyridine (99)

To a solution of 98 (0.68 g, 3.45 mmol) and triethylamine (0.72 mL, 5.18mmol) in DCM (10 mL, anhydrous) at r.t. was added mesyl chloride (0.32mL, 4.14 mmol) dropwise. After 15 min, the reaction was diluted with DCM(10 mL) and the organic layer washed with sat. NaHCO₃, dried andevaporated. The residue was redissolved in acetone (20 mL, anhydrous),lithium bromide (excess) added, and the mixture heated at reflux for 30min. The solution was then cooled and the solvent evaporated, and theresidue partitioned between EtOAc and water. The aqueous layer wasextracted twice with EtOAc and the organic layer was dried andevaporated to afford the product 99. Yield=0.70 g, 78%. ¹H NMR (CDCl₃) δ7.76 (1H, dd, J=2.6, 3.4 Hz), 7.25 (1H, dd, J=2.4, 2.4 Hz), 4.5 (2H, d,J=2.2 Hz), 4.42 (1H, sp, J=2.6, 6.0 Hz), 3.96 (3H, d, J=2.9 Hz), 1.32(6H, dd, J=3.0, 6.1 Hz).

6-Bromo-3-((5-isopropoxy-2-methoxypyridin-3-yl)methyl)-2-methoxyquinoline(100)

A mixture of 1 (0.80 g, 2.82 mmol), 99 (0.70 g, 2.69 mmol) and cesiumcarbonate (1.75 g, 5.38 mmol) in toluene (10 mL, anhydrous) and DMF (5mL, anhydrous) was purged with nitrogen. Pd(PPh₃)₄ (0.12 g, 0.11 mmol)was then added, and the mixture then heated to 80° C. under nitrogen for4 hours. The reaction was partitioned between EtOAc and water and theorganic fraction was dried and evaporated. Column chromatography (19:1hexanes/EtOAc) gave the product 100. Yield=0.57 g, 48%. ¹H NMR (CDCl₃) δ7.77 (1H, d, J=2.2 Hz), 7.71 (1H, d, J=2.9 Hz), 7.69 (1H, d, J=8.9 Hz),7.62 (1H, dd, J=2.2, 8.9 Hz), 7.56 (1H, s), 7.02 (1H, d, J=2.9 Hz), 4.38(1H, sp, J=6.0 Hz), 4.08 (3H, s), 3.92 (2H, s), 3.90 (3H, s), 1.29 (6H,d, J=6.1 Hz).

1-(6-Bromo-2-methoxyquinolin-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)butan-2-ol(101)

The product was prepared from 9 and 7 (using the General CouplingProcedure below). Flash chromatography of the crude product usingmixtures of hexanes/EtOAc in increasing eluent strength provided a 1:1mixture of diastereomers 101 as a light yellow foam (65%). ¹H NMR(CDCl₃) δ 8.71 (1H, s), 8.69 (1H, s), 8.12 (1H, bs), 7.81 (2H, m), 7.65(1H, d, J=8.9 Hz), 7.59 (1H, dd, J=2.2, 8.9 Hz), 7.53 (1H, dd, J=2.0,8.8 Hz), 7.50 (1H, d, J=8.81 Hz), 7.43 (1H, dt, J=2.4, 10.5 Hz), 7.39(1H, d, J=7.8 Hz), 7.25-7.17 (2H, m), 7.07 (1H, d, J=7.8 Hz), 7.0 (1H,d, J=8.0 Hz), 6.98-6.92 (2H, m), 6.87 (1H, dt, J=1.8, 8.4 Hz), 6.67 (1H,dt, J=1.8, 9.2 Hz), 6.55-6.31 (8H, m), 4.82 (1H, s), 4.71 (1H, s), 4.10(3H, s), 3.89 (3H, s), 3.87 (3H, s), 3.85 (6H, s), 3.83 (3H, s), 3.82(3H, s), 3.81 (3H, s), 3.79 (6H, s), 3.29-3.17 (4H, m), 2.46 (2H, br t,J=2.4 Hz), 2.16-2.02 (4H, m), 1.93 (3H, s), 1.91 (3H, s), 1.69 (1H, t,J=4.7 Hz), 1.58-1.50 (1H, m, partially obscured by water peak). One OHnot evident. Found: [M+H]=720.1

1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-4-(methylamino)butan-2-ol(102)

To a solution of 101 (2.50 g, 3.471 mmol) and in anhydrous DCM (80 mL)was added at 2° C. under nitrogen triethylamine (1.1 mL) andtrifluoroacetic anhydride (0.97 mL) sequentially. The mixture wasstirred at r.t. for 2 hours. The mixture was washed with sat. aq. NaHCO₃(2×), dried (MgSO₄) and concentrated in vacuo to afford the crudetrifluoroacetamide intermediate, which was dissolved in MeOH (55 mL). Asolution of cesium carbonate (2.83 g, 8.678 mmol) in water (5.5 mL) wasadded. The resultant brown solution was stirred at r.t. for 10 min, thenstored at 4° C. overnight. The mixture was subsequently diluted in waterand extracted with EtOAc (3×). The combined extract was washed withbrine, dried (MgSO₄) and concentrated in vacuo to furnish the crudeproduct, which was purified by column chromatography using 0-5% MeOH inDCM as eluent. The product 102 was eluted as a 1:1 mixture ofdiastereomers. ¹H NMR (CDCl₃) δ 8.66 (1H, s), 8.57 (1H, s), 7.89 (1H, d,J=2.1 Hz), 7.82 (1H, d, J=1.9 Hz), 7.67 (1H, d, J=8.9 Hz), 7.61 (1H, dd,J=2.1, 8.8 Hz), 7.53 (1H, dd, J=2.0, 8.9 Hz), 7.50 (1H, d, J=8.8 Hz),7.38-7.31 (2H, m), 7.26-7.20 (2H, m), 7.11 (1H, d, J=7.8 Hz), 7.03-6.95(1H, m), 6.90 (1H, dt, J=2.6, 8.5 Hz), 6.69 (1H, dt, J=2.6, 8.4 Hz),6.47 (4H, bs), 4.88 (1H, s), 4.72 (1H, s), 4.12 (3H, s), 3.90 (3H, s),3.87 (6H, s), 3.81 (6H, s), 2.67-2.58 (2H, m), 2.42-2.31 (2H, m), 2.25(3H, s), 2.21 (3H, s), 1.89 (1H, br t, J=12.1 Hz), 1.84-1.78 (2H, m),1.67 (1H, br d, J=14.8 Hz). Found: [M+H]=569.9

2,4-Dichlorothiazole (103)

To a mixture of thiazolidine-2,4-dione (5.00 g, 42.69 mmol) inphosphorous oxychloride (25 mL) at 0° C. was added pyridine (3.80 mL,46.96 mmol) dropwise. The mixture was then stirred at reflux for 3hours, then cooled and poured onto ice-water. The aqueous layer was thenextracted by DCM, and the combined organic layers dried and evaporated.Column chromatography with 19:1 hexanes/EtOAc afforded the product 103.Yield=0.94 g, 14%. ¹H NMR (CDCl₃) δ 7.02 (1H, s). Found: [M+H]=133.3

6-Bromo-2-methoxyquinoline-3-carbaldehyde (104)

A solution of 2,2,6,6-tetramethylpiperidine (4.28 mL, 25.2 mmol) in THF(50 mL, dist. Na) was cooled to −40° C., n-BuLi (12.60 mL, 25.2 mmol)was added and the solution was stirred at −40° C. for 15 min, thencooled to −78° C. A solution of 6-bromo-2-methoxyquinoline (5.00 g, 21mmol) in THF (50 mL, dist. Na) was added dropwise, the orange solutionwas stirred at −78° C. for 1.5 hours, then DMF (2.19 mL, 31.5 mmol) wasadded and the solution was warmed to r.t. Acetic acid (3 mL) was addedand the solvent removed, and the residue partitioned between EtOAc andwater, and the organic fraction was dried and evaporated. Columnchromatography with 4:1 hexanes/DCM followed by 1:1 hexanes/DCM followedby 1:4 hexanes/DCM gave the product 104 as a white solid. Yield=3.00 g,53%. ¹H NMR (CDCl₃) δ 10.46 (1H, s), 8.49 (1H, s), 7.99 (1H, d, J=2.1Hz), 7.79 (1H, dd, J=2.2, 8.9 Hz), 7.74 (1H, d, J=8.9 Hz), 4.18 (3H, s).

(6-Bromo-2-methoxyquinolin-3-yl)(2,4-dichlorothiazol-5-yl)methanol (105)

A solution of N,N-diisopropylamine (0.93 mL, 6.65 mmol) in THF (30 mL,dist. Na) was cooled to −40° C., n-BuLi (3.33 mL, 6.65 mmol) was addedand the solution was stirred at −40° C. for 15 min, then cooled to −78°C. A solution of 103 (0.98 g, 6.043 mmol) in THF (20 mL, dist. Na) wasadded dropwise, the orange solution was stirred at −78° C. for 2 hours,then a solution of 104 (1.78 g, 6.043 mmol) in THF (20 mL, dist. Na) wasadded. The mixture was stirred at −78° C. for 2 hours, then water (20mL) was added and the solution was allowed to warm to r.t. The solventwas removed and the residue partitioned between EtOAc and water, and theorganic fraction was dried and evaporated. Column chromatography with9:1 hexanes/EtOAc gave the product 105 as a white solid. Yield=1.98 g,78%. ¹H NMR (CDCl₃) δ 7.92-7.87 (2H, m), 7.74-7.68 (2H, m), 6.25 (1H,dd, 0.8, 4.8 Hz), 4.11 (3H, s), 3.43 (1H, d, J=4.8 Hz). Found:[M+H]=421.9.

5-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-2,4-dichlorothiazole (106)

Trifluoroacetic acid (3.35 mL, 43.80 mmol) and triethylsilane (5.74 mL,39.92 mmol) were added sequentially to a solution of 105 (1.84 g, 4.38mmol) in DCM (50 mL), the solution was stirred for 3 hours at reflux,and then the solution was cooled and added to ice water. The solutionwas partitioned between sat. aq. NaHCO₃ and DCM and the aqueous fractionwas extracted with DCM, the organic fractions were combined, dried andevaporated. Column chromatography with 19:1 hexanes/EtOAc gave theproduct 106. Yield=1.10 g, 62%. ¹H NMR (CDCl₃) δ 7.84 (1H, d, J=2.0 Hz),7.75 (1H, s), 7.70 (1H, d, J=8.9 Hz), 7.66 (1H, dd, J=2.1, 8.8 Hz), 4.13(2H, s), 4.12 (3H, s).

5-((6-Bromo-2-methoxyquinolin-3-yl)methyl)-4-chloro-2-methoxythiazole(107)

Sodium methoxide (0.20 g, 3.71 mmol) was added to a suspension of 106(1.00 g, 2.78 mmol) in MeOH (50 mL, anhydrous), and the mixture stirredat reflux for 18 hours. The solution was then cooled and the solventremoved, and the residue partitioned between EtOAc and water. Theorganic fraction was dried and evaporated. Column chromatography with19:1 hexanes/EtOAc gave the product 106. Yield=0.50 g, 45%. ¹H NMR(CDCl₃) δ 7.83 (1H, d, J=2.1 Hz), 7.70 (1H, d, J=3.6 Hz), 7.69 (1H, s),7.64 (1H, dd, J=2.2, 9.0 Hz), 4.11 (3H, s), 4.05 (3H, s), 4.03 (2H, d,J=0.8 Hz). Found: [M+H]=399.1

1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)butan-2-ol(108)

The product was prepared from 22 and 7 using the General CouplingProcedure below. Column chromatography with EtOAc:hexanes (1:1) gavefore fractions, then 108 as a mixture of isomers (66%), as a yellowfoam. ¹H NMR (CDCl₃, 400 MHz) δ 8.69 (s, 1H), 8.46 (s, 1H), 7.93 (bs,2H), 7.79 (d, J=2.0 Hz, 2H), 7.64 (d, J=8.9 Hz, 1H), 7.59-7.50 (m, 4H),7.16 (dd, J=5.9, 3.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.3 Hz,1H), 6.70-6.60 (m, 3H), 6.58-6.45 (m, 4H), 6.46-6.39 (m, 4H), 6.37-6.34(m, 1H), 5.37 (s, 1H), 5.35 (s, 1H), 4.41-4.29 (m, 4H), 4.12 (s, 3H),4.02-3.91 (m, 4H), 3.85 (s, 6H), 3.84 (s, 3H), 3.83 (s, 3H), 3.82-3.80(m, 12H), 3.79 (s, 3H), 3.25-3.19 (m, 4H), 2.49-2.41 (m, 2H), 2.15-1.95(m, 4H), 1.90 (s, 3H), 1.88 (s, 3H), 1.77-1.66 (m, 2H). Found:[M+H]=760.2.

1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(methylamino)butan-2-ol(109)

To a solution of 108 (4.13 g, 5.43 mmol) in DCM (100 mL) cooled to 0°C., was added triethylamine (1.67 mL, 11.9 mmol) and trifluoroaceticanhydride (1.51 mL, 10.9 mmol). The reaction mixture was stirred for 1h, poured onto sat. aq. NaHCO₃ (150 mL), extracted with DCM (3×100 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to obtain a yellowish residue. Thecrude material was dissolved in MeOH (150 mL) and cooled to −78° C.Cesium carbonate (4.42 g, 13.6 mmol) in water (3 mL) was added and thereaction mixture was stirred at −20° C. for 72 h. Reaction mixture wasadded water (150 mL) and extracted with EtOAc (3×100 mL). The combinedorganic layers washed with brine (100 mL), dried over Na₂SO₄, filteredand concentrated under reduced pressure to obtain a yellow residue.Column chromatography with EtOAc gave fore fractions, followed byracemate A of 109 (35%). Elution with EtOAc:MeOH (6:1) gave racemate Bof 109 (28%).

Racemate A, white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.33 (s, 1H), 7.84(d, J=2.2 Hz, 1H), 7.67 (d, J=8.9 Hz, 1H), 7.62-7.58 (m, 2H), 6.63 (t,J=8.0 Hz, 1H), 6.58-6.51 (m, 3H), 5.40 (s, 1H), 4.14 (s, 3H), 4.03-3.95(m, 4H), 3.87 (s, 6H), 2.57 (dt, J=12.5, 3.1 Hz, 1H), 2.31 (td, J=12.6,2.1 Hz, 1H), 2.16 (s, 3H), 1.85 (dt, J=15.2, 3.3 Hz, 1H), 1.72 (td,J=12.7, 2.9 Hz, 1H). (no OH, NH observed) Found: [M+H]⁼610.1.

Racemate B, white solid. ¹H NMR (CDCl₃, 400 MHz) δ 8.75 (s, 1H), 7.80(d, J=1.3 Hz, 1H), 7.52-7.48 (m, 2H), 7.04 (dd, J=6.7, 2.7 Hz, 1H),6.72-6.67 (m, 2H), 6.58 (bs, 2H), 5.37 (s, 1H), 4.42-4.28 (m, 4H), 3.84(s, 3H), 3.83 (s, 6H), 2.59 (dt, J=12.4, 3.3 Hz, 1H), 2.34-2.89 (m, 1H),2.21 (s, 3H), 1.85-1.80 (m, 2H). Found: [M+H]=610.1. (no OH, NHobserved). Found: [M+H]=610.1

1-(6-Bromo-2-methoxyquinolin-3-yl)-4-((2,4-dimethoxybenzyl)(methyl)amino)-2-(2,6-dimethoxypyridin-4-yl)-1-(5-methylthiophen-2-yl)butan-2-ol(110)

The product was prepared from 16 and 7 using the General CouplingProcedure below. Column chromatography with 9:1 hexanes:EtOAc elutedunreacted quinolone 16, while chromatography with 3:1 hexanes:EtOAc gave110 (67%) as a white foam, as a mixture of diastereomers in a ratio of1:0.95. ¹H NMR (CDCl₃) δ 8.60 (s, 1H), 8.53 (s, 0.95 H), 8.05-8.25 (bs,1.7 H), 7.81 (dd, J=11.6, 2.2 Hz, 2H), 7.66 (d, J=8.9 Hz, 1H), 7.59 (dd,J=8.8, 2.2 Hz, 1H), 7.47-7.54 (m, 1.95 H), 7.09 (d, J=8.4 Hz, 1H),6.90-6.95 (m, 1.95 H), 6.48-6.55 (m, 3.8H), 6.38-6.40 (m, 4.1 H), 6.35(bs, 1.4 H), 6.28-6.31 (m, 1.4 H), 5.15 (s, 1H), 5.08 (s, 0.95 H),4.09-4.15 (m, 3.5 H), 3.88-3.92 (m, 8.6 H), 3.75 (bs, 2.7H), 2.40-2.54(m, 2.4 H), 2.39 (d, J=0.9 Hz, 3H), 2.29 (d, J=0.9 Hz, 3H), 2.08-2.19(m, 1.6 H), 2.04-2.07 (m, 3.7 H), 1.79-1.89 (m, 4.2H), 1.59-1.59 (m, 2Hplus additional water-obscured signals). Found: [M+H]=722.4

1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(methylamino)-1-(5-methylthiophen-2-yl)butan-2-ol(111)

Triethylamine (0.63 mL, 4.5 mmol) and trifluoroacetic anhydride (0.54mL, 4.1 mmol) were added sequentially to a solution of 110 (1.459 g,2.02 mmol) in DMF (30 mL) at 0° C. The solution was stirred at r.t. for1 h and then partitioned between DCM and sat. aq. NaHCO₃, the organicfraction was dried and evaporated to give an oil which was dissolved inMeOH (50 mL) and cooled to 0° C. Cs₂CO₃ (1.64 g, 5.03 mmol) in water (10mL) was added and the mixture was stirred at 4° C. for 16 h. The mixturewas diluted with water then extracted with EtOAc, column chromatography(EtOAc) gave 111 (0.876 g, 76%) as a white foam as a mixturediastereomers, in a ratio of 1:0.7. ¹H NMR (CDCl₃) δ 8.54 (s, 1H), 8.51(s, 0.7H), 7.89 (d, J=2.2 Hz, 1H), 7.81 (d, J=1.6 Hz, 0.7 H), 7.68 (d,J=8.9 Hz, 1H), 7.62 (dd, J=8.8, 2.2 Hz, 1H), 7.47-7.53 (m, 1.5 H), 6.91(d, J=3.4 Hz, 0.7H), 6.51-6.56 (m, 3.6 H), 6.38-6.43 (m, 1.4H),6.29-6.33 (m, 1H), 5.18 (s, 1H), 5.09 (s, 0.7 H), 4.13 (s, 3.8H), 3.92(s, 2.1H), 3.91 (s, 5.6H), 3.78 (m, 4.2H), 2.67 (dt, J=9.2, 3.3 Hz, 1H),2.55 (dt, J=12.6, 3.0 Hz, 1H), 2.34-2.45 (m, 3.1H), 2.18-2.33 (m, 6.7H),2.16 (s, 3H), 1.67-1.82 (m, 2.6H), 1.42-1.62 (m, 4H plus additionalwater-obscured signals). Found: [M+H]=572.1

1-(Benzofuran-7-yl)ethan-1-ol (112)

A solution of 7-bromobenzofuran (2.05 g, 10.4 mmol) in dry THF (20 mL)was prepared. Approximately 4 mL of this solution was added to a flaskcontaining magnesium (0.75 g, 30.9 mmol) and the mixture was agitateduntil an exothermic reaction occurred. The remaining solution was addedand the mixture was refluxed for 1 h, cooled and transferred by cannulato a dry flask. The solution was cooled to 0° C. and acetaldehyde (0.70mL, 12.3 mmol) was added, the mixture was stirred at 0° C. for 1 h thenpartitioned between EtOAc and water, the organic fractions were driedand evaporated. Column chromatography with hexanes:DCM (1:1) eluted nonpolar impurities, elution with DCM gave 112 (1.21 g, 72%). ¹H NMR(CDCl₃) δ 7.64 (d, J=2.2 Hz, 1H), 7.52 (dd, J=7.7, 1.2 Hz, 1H), 7.34(bd, J=7.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 1H), 6.79 (d, J=2.2 Hz, 1H), 5.38(td, J=6.5, 4.8 Hz, 1H), 2.16 (d, J=4.8 Hz, 1H), 1.67 (d, J=6.5 Hz, 3H).Found: [M−H₂O]=145.

1-(Benzofuran-7-yl)ethan-1-one (113)

A mixture of 112 (1.16 g, 7.15 mmol) and MnO₂ (3.10 g, 35.6 mmol) inbenzene (40 mL) was refluxed for 1 h, filtered through Celite and thesolvent was evaporated. Column chromatography with hexanes:DCM (3:1 to1:1) gave 113 (0.98 g, 86%). ¹H NMR (CDCl₃) δ 7.92 (dd, J=7.6, 1.2 Hz,1H), 7.81 (dd, J=7.7, 1.2 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.33 (t,J=7.7 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 2.86 (s, 3H). Found: [M+H]=161.1.

1-(Benzofuran-7-yl)-3-(dimethylamino)propan-1-one (114)

A mixture of 113 (4.95 g, 30.9 mmol), dimethylamine HCl (3.78 g, 46.4mmol) and paraformaldehyde (1.39 g, 46.3 mmol) in EtOH (50 mL) and HCl(0.5 mL, 12 M, 6 mmol) was refluxed in a sealed tube for 18 h. Thesolvent was evaporated and the solid residue was triturated with Et₂Oand filtered. The solid was washed with Et₂O, dissolved in water andbasified with 2M NaOH, then extracted with EtOAc (3×100 mL). The organicfractions were dried and evaporated to give 114 (4.63 g, 69%). ¹H NMR(CDCl₃) δ 7.93 (dd, J=7.6, 1.1 Hz, 1H), 7.81 (dd, J=7.7, 1.3 Hz, 1H),7.74 (d, J=2.2 Hz, 1H), 7.33 (t, J=7.7 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H),3.46 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.32 (s, 6H). Found:[M+H]=218.2.

(5,6-Dimethoxypyridin-3-yl)methanol (115)

n-BuLi (4.90 mL, 2.0 M in cyclohexanes, 35.2 mmol) was added to asolution of 5-bromo-2,3-dimethoxypyridine (7.00 g, 32.1 mmol) in dry THF(100 mL) at −35° C., the cream coloured precipitate was stirred at −35°C. for 0.5 h then DMF (4.90 mL, 63.7 mmol) was added. The mixture wasstirred at −35° C. for 1 h, then quenched with water and partitionedbetween EtOAc and water, the organic fraction was dried and evaporated.The crude aldehyde was dissolved in MeOH (50 mL) and cooled to −40° C.,NaBH₄ (1.20 g, 32 mmol) was added and the mixture was stirred at −40° C.for 1 h and then quenched with water. The mixture was partitionedbetween EtOAc and water, the organic fractions were dried andevaporated. Column chromatography using hexanes:EtOAc (2:1) gave 115(4.02 g, 74%). ¹H NMR (CDCl₃) δ 7.67 (d, J=1.9 Hz, 1H), 7.13 (d, J=1.9Hz, 1H), 4.63 (d, J=5.4 Hz, 2H), 4.02 (s, 3H), 3.90 (s, 3H), 1.77 (t,J=5.4 Hz, 1H). Found: [M+H]=170.2.

(5-Bromomethyl)-2,3-dimethoxypyridine (116)

A solution of 115 (3.98 g, 23.6 mmol) in DCM (anhydrous, 80 mL) at 0° C.was treated with triethylamine (6.6 mL, 47.4 mmol) and then mesylchloride (2.73 mL, 35.3 mmol), the mixture was stirred at 0° C. for 1 hand then partitioned between DCM and water. The organic fraction wasdried and evaporated and the residue was dissolved in acetone (100 mL),LiBr (117 mmol) was added and the mixture was refluxed for 1 h and thenevaporated. The residue was partitioned between DCM and water; theorganic fraction was dried and evaporated. Column chromatography (DCM)gave 116 (3.36 g, 61%) which was contaminated with the correspondingchloro derivative (0.30 g, 7%). ¹H NMR (CDCl₃) δ 7.73 (d, J=2.0 Hz, 1H),7.07 (d, J=2.0 Hz, 1H), 4.47 (s, 2H), 4.02 (s, 3H), 3.90 (s, 3H). Found:[M+H]=232.4

6-Bromo-3-((5,6-dimethoxypyridin-3-yl)methyl)-2-methoxyquinoline (117)

A mixture of 1 (4.02 g, 14.3 mmmol), 116 (3.34 g, 14.4 mmol) and Cs₂CO₃(9.3 g, 28.5 mmol) in toluene (80 mL, anhydrous) and DMF (40 mL,anhydrous) was purged with nitrogen. Pd(PPh₃)₄ (0.33 g, 0.3 mmol) wasadded, the mixture was purged with nitrogen, then heated to 80° C. undernitrogen for 4 h. The reaction was partitioned between EtOAc and waterand the organic fraction was dried and evaporated. Column chromatography(95:5 DCM:EtOAc) gave the product which was recrystallized from MeOH togive 117 (3.85 g, 69%). ¹H NMR (CDCl₃) δ 7.77 (d, J=2.2 Hz, 1H), 7.70(d, J=8.9 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.63 (dd, J=8.9, 2.2 Hz, 1H),7.52 (s, 1H), 6.92 (d, J=1.9 Hz, 1H), 4.09 (s, 3H), 4.02 (s, 3H), 3.95(s, 2H), 3.83 (s, 3H). Found: [M+H]=389.1

(2,3-Dimethoxypyridin-4-yl)methanol (118)

A warm solution of 2,3-dimethoxyisonicotinaldehyde (0.68 g, 4.10 mmol)in EtOH (5 mL) was added dropwise to a suspension of NaBH₄ (0.08 g, 2.04mmol) in EtOH (10 mL) at −40° C., gas evolution occurred and the mixturewas stirred at −40° C. for 45 min The mixture was quenched with brine(10 mL) and diluted with water (10 mL), then extracted with ether (3×50mL). Column chromatography (1:1 hexanes:EtOAc) gave 118 (0.69 g, 98%).¹H NMR (CDCl₃) δ 7.89 (d, J=5.1 Hz, 1H), 6.93 (d, J=5.1 Hz, 1H), 4.73(d, J=6.1 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 3H), 2.15 (t, J=6.1 Hz, 1H).Found: [M+H]=170.2.

4-(Bromomethyl)-2,3-dimethoxypyridine (119)

A solution of 118 (2.83 g, 16.8 mmol) and triethylamine (4.70 mL, 33.7mmol) in DCM (50 mL, anhydrous) was cooled to 0° C., then treated withmesyl chloride (1.95 mL, 25.2 mmol). The cloudy suspension was stirredat 0° C. for 1 h and partitioned between DCM and water. The organicfraction was dried and evaporated to give the crude mesylate. The crudemesylate was dissolved in acetone (100 mL) and LiBr (14.5 g, 167 mmol)was added. The mixture was refluxed for 1 h, evaporated and the residuewas partitioned between DCM and water. The organic fraction was driedand evaporated. Column chromatography (DCM) gave 119 (3.53 g, 91%). ¹HNMR (CDCl₃) δ 7.85 (d, J=5.2 Hz, 1H), 6.87 (d, J=5.2 Hz, 1H), 4.45 (s,2H), 4.01 (s, 3H), 3.95 (s, 3H). Found: [M+H]=232.4.

6-Bromo-3-((2,3-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (120)

A mixture of 1 (10.28 g, 36.5 mmol), 119 (8.64 g, 36.5 mmol) and Cs₂CO₃(24.0 g, 73.7 mmol) in DMF:toluene (1:2, 200 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.84 g, 0.73 mmol) was added and the mixture washeated to 80° C. for 3 h under nitrogen. The mixture was partitionedbetween EtOAc and water and the aqueous layer was extracted with EtOAc.The organic fraction was dried and evaporated, column chromatographyusing a gradient of 3:1 hexanes:DCM to 95:5 DCM:EtOAc gave 120 (8.65 g,61%). ¹HNMR (CDCl₃) δ 7.80 (d, J=5.2 Hz, 1H), 7.77 (d, J=2.2 Hz, 1H),7.69 (d, J=8.9 Hz, 1H), 7.62 (dd, J=8.9, 2.2 Hz, 1H), 7.53 (s, 1H), 6.66(d, J=5.2 Hz, 1H), 4.07 (s, 3H), 4.03 (s, 2H), 4.02 (s, 3H), 3.80 (s,3H). Found: [M+H]=389.1.

N-Methoxy-N-methylbenzofuran-2-carboxamide (121)

Oxalyl chloride (3.13 mL, 3.70 mmol) was added to a suspension ofbenzofuran-2-carboxylic acid (5.00 g, 3.08 mmol) in DCM (100 mL,anhydrous) and DMF (0.1 mL, 1.3 mmol) at r.t. The mixture was stirred atr.t. for 1 h to give a colourless solution which was cooled to 0° C.N,O-Dimethylhydroxylamine hydrochloride (3.31 g, 3.39 mmol) and pyridine(7.5 mL, 9.27 mmol) were added sequentially and the mixture was stirredat r.t. for 18 h, then partitioned between EtOAc and sat. aq. NaHCO₃.Column chromatography (3:1 hexanes:EtOAc) gave 121 (6.32 g, 100%). ¹HNMR (CDCl₃) δ 7.69 (ddd, 7.9, 1.2, 0.7 Hz, 1H), 7.61 (ddd, J=8.4, 1.7,0.9 Hz, 1H), 7.51 (d, J=1.0 Hz, 1H), 7.48 (ddd, J=7.9, 7.2, 1.3 Hz, 1H),7.30 (ddd, J=7.5, 7.3, 0.9 Hz, 1H), 3.84 (s, 3H), 3.43 (s, 3H). Found:[M+H]=206.2.

1-(Benzofuran-2-yl)-3-(dimethylamino)propan-1-one (122)

Vinylmagnesium bromide (58 mL, 58 mmol, 1 M in THF) was added to asolution of 121 (3.95 g, 19.2 mmol) in THF (200 mL, anhydrous) at 0° C.,the brown solution was warmed to r.t. for 1 h then dimethylamine (58 mL,116 mmol, 2 M in THF) and water (40 mL) were added. The solution wasstirred at r.t. for 1 h, and then partitioned between EtOAc and water.The solution was dried and evaporated to give 122 (4.17 g, 100%). ¹H NMR(CDCl₃) δ 7.72 (ddd, J=7.9, 1.0, 0.8 Hz, 1H), 7.59 (dd, J=8.4, 0.8 Hz,1H), 7.53 (d, J=0.9 Hz, 1H), 7.48 (ddd, J=7.8, 7.2, 1.2 Hz, 1H), 7.32(ddd, J=7.5, 7.2, 1.0 Hz, 1H), 3.14 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5Hz, 2H), 2.31 (s, 6H). Found: [M+H]=218.2.

Methyl benzofuran-5-carboxylate (123)

A mixture of 5-bromobenzofuran (4.00 g, 20.3 mmol), DPPP (0.42 g, 1mmol), triethylamine (6.3 mL, 45 mmol) and Pd(OAc)₂ (0.23 g, 1 mmol) inDMSO (30 mL) and MeOH (30 mL) in a Berghof pressure reactor wasevacuated then purged three times with carbon monoxide. The mixture washeated to 80° C. for 18 h under 60 psi of carbon monoxide pressure,cooled and partitioned between EtOAc and water. Column chromatographywith 3:1 hexanes:DCM eluted traces of impurities while elution with DCMgave 123 (2.77 g, 78%). ¹H NMR (CDCl₃) δ 8.35 (d, J=1.4 Hz, 1H), 8.03(dd, J=8.7, 1.7 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.53 (dt, J=8.7, 0.8Hz, 1H), 6.84 (dd, J=2.2, 1.0 Hz, 1H), 3.94 (s, 3H).

Benzofuran-5-carboxylic acid (124)

A solution of LiOH (1.13 g, 47.2 mmol) in water (20 mL) was added to asolution of 123 (2.77 g, 15.7 mmol) in THF (40 mL) and MeOH (40 mL) andthe solution was stirred at r.t. for 18 h and then evaporated. Theresidue was dissolved in water (50 mL) and acidified with conc. HCl topH 2. The precipitate was dissolved in EtOAc, the organic fraction wasdried and evaporated to give 124 (2.49 g, 98%). ¹H NMR (DMSO-d₆) δ 12.86(s, 1H), 8.30 (d, J=1.4 Hz, 1H), 8.10 (d, J=2.2 Hz, 1H), 7.92 (dd,J=8.6, 1.8 Hz, 1H), 7.68 (dt, J=8.6, 0.7 Hz, 1H), 7.08 (dd, J=2.2, 0.9Hz, 1H).

N-methoxy-N-methylbenzofuran-5-carboxamide (125)

Oxalyl chloride (1.55 mL, 18.3 mmol) was added to a suspension of 124(2.48 g, 15.3 mmol) in DCM (100 mL, anhydrous) and DMF (0.05 mL, 0.64mmol) at r.t. The mixture was stirred at r.t. for 1 h to give acolourless solution which was cooled to 0° C. N,O-Dimethylhydroxylaminehydrochloride (1.64 g, 16.8 mmol) and pyridine (3.71 mL, 45.9 mmol) wereadded sequentially and the mixture was stirred at r.t. for 18 h, thenpartitioned between EtOAc and sat. aq. NaHCO₃. Column chromatographywith 95:5 DCM:EtOAc gave 125 (2.28 g, 73%) as a pale brown oil. ¹H NMR(CDCl₃) δ 7.99 (d, J=1.4 Hz, 1H), 7.65-7.69 (m, 2H), 7.52 (dt, J=8.6,0.6 Hz, 1H), 6.82 (dd, J=2.2, 0.9 Hz, 1H), 3.56 (s, 3H), 3.39 (s, 3H).Found: [M+H]=206.2.

1-(Benzofuran-5-yl)-3-(dimethylamino)propan-1-one (126)

Vinylmagnesium bromide (33.2 mL, 1 M in THF, 33.2 mmol) was added to asolution of 125 (2.27 g, 11.1 mmol) in THF (100 mL, dist. Na) at 0° C.,the brown solution was stirred at 0° C. for 1 h then dimethylamine (33.2mL, 2 M in THF, 66.4 mmol) and water (20 mL) were added. The solutionwas stirred at r.t. for 1 h, and then partitioned between EtOAc andwater. The solution was dried and evaporated to give 126 (2.33 g, 97%).¹H NMR (CDCl₃) δ 8.27 (d, J=1.8 Hz, 1H), 7.98 (dd, J=8.7, 1.8 Hz, 1H),7.70 (d, J=2.2 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 6.84 (dd, J=2.2, 0.8 Hz,1H), 3.22 (t, J=7.1 Hz, 2H), 2.80 (t, J=7.1 Hz, 2H), 2.31 (s, 6H).Found: [M+H]=218.2.

(2,6-Diethoxypyridin-4-yl)methanol (127)

Trimethylborate (3.88 mL, 34.2 mmol) and borane-dimethylsulfide (3.25mL, 34.3 mmol) were added sequentially to a solution of2,6-diethoxyisonicotinic acid (2) (2.41 g, 11.4 mmol) in THF (100 mL,dist. Na) at 0° C. and the mixture was stirred at r.t. for 18 hr. Thesolution was cooled to 0° C. and methanol was cautiously added to quenchexcess borane. Removal of the solvent gave a solid which was partitionedbetween EtOAc and water, the organic fraction was dried and evaporated.Column chromatography (3:1 hexanes:EtOAc) gave 127 (2.13 g, 95%). ¹H NMR(DMSO-d₆) δ 6.27 (d, J=0.6 Hz, 2H), 4.62 (d, J=6.2 Hz, 2H), 4.31 (q,J=7.1 Hz, 4H), 1.72 (t, J=6.2 Hz, 1H), 1.38 (t, J=7.1 Hz, 6H). Found:[M+H]=198.1.

4-(Bromomethyl)-2,6-diethoxypyridine (128)

A solution of 127 (2.07 g, 10.5 mmol) in DCM (100 mL, anhydrous) at 0°C. was treated sequentially with triethylamine (2.93 mL, 21.0 mmol) andmesyl chloride (1.22 mL, 15.8 mmol), the mixture was stirred at 0° C.for 1 h then partitioned between DCM and water. The organic fraction wasdried and evaporated and the residue was dissolved in acetone (100 mL),LiBr (9.15 g, 105 mmol) was added and the mixture was refluxed for 1 hthen evaporated. The residue was partitioned between DCM and water andthe organic fraction was dried and evaporated. Column chromatography(DCM) gave 128 (2.63 g, 92%). ¹H NMR (CDCl₃) δ 6.28 (s, 2H), 4.31 (q,J=7.1 Hz, 4H), 4.28 (s, 2H), 1.38 (t, J=7.1 Hz, 6H). Found: [M+H]=260.5.

6-Bromo-3-((2,6-diethoxypyridin-4-yl)methyl)-2-methoxyquinoline (129)

A mixture of 1 (2.20 g, 7.80 mmol), 128 (2.13 g, 8.20 mmol) and Cs₂CO₃(5.13 g, 15.6 mmol) in toluene (40 mL) and DMF (20 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.18 g, 0.156 mmol) was added, the mixture waspurged with nitrogen, then heated to 80° C. under nitrogen for 3 h. Thereaction was partitioned between EtOAc and water and the organicfraction was dried and evaporated. Column chromatography with 3:1hexanes:DCM eluted non polar impurities, elution with 1:1 hexanes:DCMgave 129 (2.35 g, 72%). ¹H NMR (CDCl₃) δ 7.77 (d, J=2.2 Hz, 1H), 7.69(d, J=8.0 Hz, 1H), 7.62 (dd, J=8.8, 2.2 Hz, 1H), 7.58 (s, 1H), 6.13 (s,2H), 4.29 (q, J=7.1 Hz, 4H), 4.06 (s, 3H), 3.90 (s, 2H), 1.36 (t, J=7.1Hz, 6H). Found: [M+H]=417.1.

Benzofuran-4-yl trifluoromethanesulfonate (130)

A solution of benzofuran-4-ol (2.61 g, 19.5 mmol), DMAP (0.060 g, 0.49mmol) and pyridine (2.37 mL, 29.3 mmol) in DCM (60 mL, anhydrous) at 0°C. was treated with TFAA (4.92 mL, 29.2 mmol) and then stirred at 0° C.for 2 h. The mixture was partitioned between DCM and water; the organicfractions were dried and evaporated. Column chromatography (hexanes)gave 130 (3.93 g, 76%). ¹H NMR (CDCl₃) δ 7.70 (d, J=2.3 Hz, 1H), 7.56(d, J=8.2 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H), 6.90(dd, J=1.9, 1.0 Hz, 1H). Found: [M+H]=267.0.

Methyl benzofuran-4-carboxylate (131)

A mixture of 130 (3.88 g, 14.6 mmol), DPPP (0.180 g, 0.44 mmol),triethylamine (4.07 mL, 29.2 mmol) and Pd(OAc)₂ (0.098 g, 0.44 mmol) inDMSO (50 mL) and MeOH (50 mL) in a Berghof pressure reactor wasevacuated then purged three times with carbon monoxide. The mixture washeated to 80° C. for 18 h under 60 psi of carbon monoxide pressure,cooled and partitioned between EtOAc and water. Column chromatographywith 3:1 hexanes:DCM eluted traces of impurities while elution with DCMgave 131 (2.08 g, 81%). ¹H NMR (CDCl₃) δ 7.99 (dd, J=7.7, 0.9 Hz, 1H),7.74 (d, J=2.2 Hz, 1H), 7.70 (dt, J=8.2, 0.9 Hz, 1H), 7.33-7.39 (m, 2H),3.99 (s, 3H).

Benzofuran-4-caroxylic acid (132)

A solution of LiOH (1.44 g, 34.3 mmol) in water (20 mL) was added to asolution of 131 (2.02 g, 11.4 mmol) in THF (20 mL) and MeOH (20 mL) andthe solution was stirred at r.t. for 16 h and then evaporated. Theresidue was dissolved in water (50 mL) and acidified with conc. HCl andthe precipitate was filtered and dried to give 132 (1.83 g, 99%). ¹H NMR(DMSO-d₆) δ 13.10 (s, 1H), 8.14 (d, J=2.1 Hz, 1H), 7.85-7.91 (m, 2H),7.43 (t, J=7.9 Hz, 1H), 7.33 (dd, J=2.1, 1.0 Hz, 1H). Found:[M−H]=161.1.

N-Methoxy-N-methylbenzofuran-4-carboxamide (133)

Oxalyl chloride (1.14 mL, 13.5 mmol) was added to a suspension of 132(1.82 g, 11.2 mmol) in DCM (100 mL, anhydrous) and DMF (0.2 mL, 2.5mmol) at r.t. The mixture was stirred at r.t. for 1 h to give acolourless solution which was cooled to 0° C. N,O-Dimethylhydroxylaminehydrochloride (1.31 g, 13.5 mmol) and pyridine (2.72 mL, 33.6 mmol) wereadded sequentially and the mixture was stirred at r.t. for 18 h, thenpartitioned between DCM and water. Column chromatography with 95:5DCM:EtOAc gave 133 (2.13 g, 93%). ¹H NMR (CDCl₃) δ 7.68 (d, J=2.2 Hz,1H), 7.59 (dt, J=8.3, 0.8 Hz, 1H), 7.51 (dd, J=7.5, 0.9 Hz, 1H), 7.32(t, J=7.9 Hz, 1H), 6.95 (dd, J=2.2, 0.9 Hz, 1H), 3.56 (s, 3H). 3.40 (s,3H). Found: [M+H]=206.2.

1-(Benzofuran-4-yl)-3-(dimethylamino)propan-1-one (134)

Vinylmagnesium bromide (20.5 mL, 20.5 mmol) was added to a solution of133 (2.11 g, 10.3 mmol) in THF (100 mL, dist. Na) at 0° C., the brownsolution was warmed to r.t. for 1 h, then dimethylamine in THF (20.5 mL,2 M, 41 mmol) and water (20 mL) were added. The solution was stirred atr.t. for 1 h, then partitioned between EtOAc and water. The solution wasdried and evaporated to give 134 (1.83 g, 82%). ¹H NMR (CDCl₃) δ 7.86(dd, J=7.6, 0.6 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.71 (dt, J=8.2, 0.8Hz, 1H), 7.55 (dd, J=2.2, 1.0 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 3.27 (t,J=7.1 Hz, 2H), 2.82 (t, J=7.1 Hz, 2H), 2.32 (s, 6H). Found: [M+H]=218.2.

Methyl benzo[b]thiophene-7-carboxylate (135)

A suspension of 2-mercaptobenzoic acid (10.00 g, 6.49 mmol) in EtOH (50mL) was treated with 2-bromo-1,1,-dimethoxyethane (10 mL, 8.5 mmol) andNaOH (5.70 g, 14.3 mmol) and the mixture was refluxed for 3 h. Thesolvent was evaporated and the residue was dissolved in DMF (100 mL),MeI (6.0 mL, 9.6 mmol) and K₂CO₃ (27.0 g, 19.5 mmol) were added and themixture was stirred at r.t. for 1 h, then partitioned between EtOAc andwater, the organic layer was washed with water and brine, dried andevaporated. The residue was dissolved in chlorobenzene (50 mL),polyphosphoric acid (33 g) was added and the mixture was heated to 130°C. for 2 h. The gummy residue was poured onto ice and extracted withEtOAc, the organic fractions were washed with water, brine, dried andevaporated. Column chromatography with 10:1 hexanes:EtOAc gave 135 (6.46g, 52%). ¹H NMR (CDCl₃) δ 8.12 (ddd, J=6.9, 1.0, 0.4 Hz, 1H), 8.03 (dd,J=7.9, 1.2 Hz, 1H), 7.58 (dd, J=5.6, 0.3 Hz, 1H), 7.46 (t, J=7.6 Hz,1H), 7.40 (d, J=5.6 Hz, 1H), 4.03 (s, 3H).

Benzo[b]thiophene-7-carboxylic acid (136)

A solution of LiOH (2.10 g, 87.7 mmol) in water (25 mL) was added to asolution of 135 (5.61 g, 29.2 mmol) in THF (50 mL) and MeOH (50 mL) andthe solution was stirred at r.t. for 18 h then evaporated. The residuewas dissolved in water (150 mL) and acidified to pH 2 with conc. HCl.The precipitate was extracted into EtOAc, the organic fractions weredried and evaporated to give 136 (4.69 g, 90%). ¹H NMR (DMSO-d₆) δ 13.42(s, 1H), 8.16 (d, J=7.8 Hz, 1H), 8.04 (d, J=7.4 Hz, 1H), 7.86 (d, J=5.6Hz, 1H), 7.50-7.56 (m, 2H). Found: [M−H]=177.1.

N-Methoxy-N-methylbenzo[b]thiophene-7-carboxamide (137)

Oxalyl chloride (2.67 mL, 31.6 mmol) was added to a suspension of 136(4.69 g, 26.3 mmol) in DCM (200 mL, anhydrous) and DMF (0.5 mL, 6.5mmol) at r.t. The mixture was stirred at r.t. for 1 h then cooled to 0°C. N,O-Dimethylhydroxylamine hydrochloride (3.08 g, 31.6 mmol) andpyridine (6.38 mL, 78.9 mmol) were added sequentially and the mixturewas stirred at r.t. for 18 h, then partitioned between EtOAc and sat.aq. NaHCO₃. Column chromatography with DCM gave 137 (5.48 g, 94%). ¹HNMR (CDCl₃) δ 7.92 (dd, J=7.9, 1.0 Hz, 1H), 7.81 (dd, J=7.5, 0.5 Hz,1H), 7.53 (dd, J=5.5, 0.3 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.37 (d,J=5.5 Hz, 1H), 3.61 (s, 3H), 3.43 (s, 3H). Found: [M+H]=222.1.

1-(Benzo[b]thiophen-7-yl)-3-(dimethylamino)propan-1-one (138)

Vinylmagnesium bromide (49 mL, 1 M, 49 mmol) was added to a solution of137 (5.38 g, 24.3 mmol) in THFE (250 mL, dist. Na) at 0° C., the brownsolution was warmed to r.t. for 1 h and then dimethylamine in THF (49mL, 2 M, 98 mmol) and water (25 mL) were added. The solution was stirredat r.t. for 1 h, then partitioned between EtOAc and water. The solutionwas dried and evaporated to give 138 (5.45 g, 96%). ¹H NMR (CDCl₃) δ8.07 (d, J=7.8 Hz, 2H), 7.64 (d, J=5.6 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H),7.41 (d, J=5.6 Hz, 1H), 3.34 (t, J=7.7 Hz, 2H), 2.87 (t, J=7.7 Hz, 2H),2.33 (s, 6H). Found: [M+H]=234.1.

Methyl 2-hydroxy-6-methoxyisonicotinate (139)

A suspension of 2,6-dihydroxyisonicotinic acid (10.00 g, 64.5 mmol) inMeOH (60 mL) was treated dropwise with H₂SO₄ (10 mL, 18.4 M, 184 mmol).The solution was refluxed for 72 h and then evaporated. The residue wastreated with sat. aq. NaHCO₃ to pH 8 and extracted with EtOAc (3×200mL). The organic extracts were washed with sat. aq. NaHCO₃ and brine,then dried and evaporated to give 139 (3.55 g, 30%). ¹H NMR (DMSO-d₆) δ11.2 (bs, 1H), 6.61 (bs, 2H), 3.84 (s, 3H), 3.83 (s, 3H). Found:[M+H]=184.2.

Methyl 2-isopropoxy-6-methoxyisonicotinate (140)

A solution of 139 (5.04 g, 27.5 mmol) in DMF (100 mL, anhydrous) wastreated with K₂CO₃ (4.75 g, 34.4 mmol) and then 2-iodopropane (3.43 mL,34.4 mmol). The mixture was stirred at r.t. for 24 h, more 2-iodopropane(3.43 mL, 34.3 mmol) was added and the mixture was stirred for a further72 h then partitioned between EtOAc and water and the aqueous layer wasextracted further with EtOAc. The organic fractions were washed withwater, dried and evaporated. Chromatography (DCM) gave 140 (6.21 g,100%). ¹H NMR (CDCl₃) δ 6.81 (s, 2H), 5.24 (sp, J=6.2 Hz, 1H), 3.92 (s,3H), 3.90 (s, 3H), 1.36 (d, J=6.2 Hz, 6H). Found: [M+H]=226.2.

2-Isopropoxy-6-methoxyisonicotinic acid (141)

A solution of LiOH (1.98 g, 82.7 mmol) in water (60 mL) was added to asolution of 140 (6.20 g, 27.5 mmol) in MeOH (60 mL) and THF (60 mL) andthe solution was stirred at r.t. for 18 h and then evaporated. Theresidue was dissolved in water (150 mL) and acidified to pH 3 with 2 MHCl. The precipitate was filtered and dried to give 141 (5.33 g, 92%) asa white solid. ¹H NMR (DMSO-d₆) δ 13.50 (bs, 1H), 6.70 (d, J=1.0 Hz,1H), 6.66 (d, J=1.0 Hz, 1H), 5.20 (sp, J=6.2 Hz, 1H), 3.86 (s, 3H), 1.31(d, J=6.2 Hz, 6H). Found: [M+H]=212.1.

2-Isopropoxy-N,6-dimethoxy-N-methylisonicotinamide (142)

Oxalyl chloride (1.75 mL, 20.7 mmol) was added to 141 (3.65 g, 17.3mmol) in DCM (100 mL, anhydrous) and DMF (0.3 mL) at r.t. The mixturewas stirred at r.t. for 1 h to give a colourless solution which wascooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (2.03 g, 20.8mmol) and pyridine (4.2 mL, 51.9 mmol) were added sequentially and themixture was stirred at r.t. for 18 h, then partitioned between EtOAc andwater. Column chromatography with 3:1 hexanes:EtOAc gave 142 (4.58 g,100%) which was used directly in the subsequent synthesis of 143. ¹H NMR(CDCl₃) δ 6.42 (s, 1H), 6.41 (s, 1H), 5.24 (sp, J=6.2 Hz, 1H), 3.90 (s,3H), 3.60 (bs, 3H), 3.32 (bs, 3H), 1.35 (d, J=6.2 Hz, 6H). Found:[M+H]=255.2.

3-(Dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)propan-1-one(143)

Vinylmagnesium bromide (36 mL, 1 M, 36 mmol) was added to a solution of142 (4.54 g, 17.9 mmol) in THF (200 mL, dist. Na) at 0° C., the brownsolution was warmed to r.t. for 1 h, then dimethylamine in THF (36 mL, 2M, 72 mmol) and water (30 mL) were added. The solution was stirred atr.t. for 1 h and then partitioned between EtOAc and water. Columnchromatography using a gradient of 97.5:2.5 DCM:MeOH to 95:5 DCM:MeOHgave 143 (3.58 g, 75%). ¹H NMR (CDCl₃) δ 6.70 (d, J=1.0 Hz, 1H), 6.69(d, J=1.0 Hz, 1H), 5.25 (sp, J=6.2 Hz, 1H), 3.92 (s, 3H), 3.05 (t, J=7.4Hz, 2H), 2.72 (t, J=7.4 Hz, 2H), 2.26 (s, 6H), 1.36 (d, J=6.2 Hz, 6H).Found: [M+H]=267.2.

Methyl 2-ethoxy-6-methoxyisonicotinate (144)

A solution of 139 (6.96 g, 38.0 mmol) in DMF (100 mL, anhydrous) wastreated with K₂CO₃ (6.57 g, 47.6 mmol) and then iodoethane (3.85 mL,47.6 mmol). The mixture was stirred at r.t. for 24 h, partitionedbetween EtOAc and water and the aqueous layer was extracted with EtOAc.The organic fractions were washed with water, dried and evaporated,chromatography (DCM) gave 144 (6.20 g, 77%). ¹H NMR (CDCl₃) δ 6.84 (s,2H), 4.35 (q, J=7.1 Hz, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 1.40 (t, J=7.1Hz, 3H). Found: [M+H]=212.1.

2-Ethoxy-6-methoxyisonicotinic acid (145)

A solution of LiOH (2.10 g, 87.7 mmol) in water (60 mL) was added to asolution of 144 (6.20 g, 29.4 mmol) in MeOH (60 mL) and THF (60 mL), thesolution was stirred at r.t. for 18 h and then evaporated. The residuewas dissolved in water (150 mL) and acidified to pH 3 with 2 M HCl. Theprecipitate was filtered and dried to give 145 (5.61 g, 97%) as a whitesolid. ¹H NMR (DMSO-d₆) δ 13.54 (bs, 1H), 6.73 (d, J=1.0 Hz, 1H), 6.71(d, J=1.0 Hz, 1H), 4.32 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 1.33 (t, J=7.0Hz, 3H). Found: [M+H]=198.2.

2-Ethoxy-N,6-dimethoxy-N-methylisonicotinamide (146)

Oxalyl chloride (2.18 mL, 25.8 mmol) was added to a suspension of 145(4.23 g, 21.5 mmol) in DCM (100 mL, anhydrous) and DMF (0.3 mL) at r.t.The mixture was stirred at r.t. for 1 h to give a colourless solutionwhich was cooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (2.51g, 25.8 mmol) and pyridine (5.2 mL, 64.3 mmol) were added sequentiallyand the mixture was stirred at r.t. for 18 h, then partitioned betweenDCM and sat. aq. NaHCO₃. Column chromatography with 3:1 hexanes:EtOAcgave 146 (5.02 g, 97%). ¹H NMR (CDCl₃) δ 6.46 (s, 1H), 6.45 (s, 1H),4.35 (q, J=7.1 Hz, 2H), 3.92 (s, 3H), 3.59 (bs, 3H), 3.32 (s, 3H), 1.40(t, J=7.1 Hz, 3H). Found: [M+H]=241.1.

3-(Dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)propan-1-one (147)

Vinylmagnesium bromide (16.6 mL, 1 M, 16.6 mmol) was added to a solutionof 146 (2.00 g, 8.30 mmol) in THF (100 mL, dist. Na) at 0° C., the brownsolution was warmed to r.t. for 1 h then dimethylamine in THF (2M, 16.6mL, 33.2 mmol) and water (25 mL) were added. The solution was stirred atr.t. for 1 h, then partitioned between EtOAc and water. The solution wasdried and evaporated, column chromatography of the residue (95:5DCM:MeOH) gave 147 (1.40 g, 67%). ¹H NMR (CDCl₃) δ 6.73 (s, 1H), 6.72(s, 1H), 4.37 (q, J=7.0 Hz, 2H), 3.93 (s, 3H), 3.06 (t, J=7.4 Hz, 2H),2.72 (t, J=7.4 Hz, 2H), 2.27 (s, 6H), 1.41 (t, J=7.0 Hz, 3H). Found:[M+H]=253.2.

(2-Isopropoxy-6-methoxypyridin-4-yl)methanol (148)

Trimethylborate (6.81 mL, 59.6 mmol) and borane dimethylsulfide complex(5.66 mL, 59.7 mmol) were added sequentially to a solution of 141 (6.30g, 29.8 mmol) in THF (100 mL, dist. Na) at 0° C., the mixture wasstirred at r.t. for 18 hr. The solution was cooled to 0° C. and quenchedwith methanol. Removal of the solvent gave a white solid, which waspartitioned between EtOAc and water, the organic fraction was dried andevaporated to give 148 (5.86 g, 99%). ¹H NMR (CDCl₃) δ 6.26 (t, J=0.8Hz, 1H), 6.25 (t, J=0.8 Hz, 1H), 5.23 (sp, J=6.2 Hz, 1H), 4.61 (d, J=6.2Hz, 2H), 3.88 (s, 3H), 1.73 (t, J=6.2 Hz, 1H), 1.34 (d, J=6.2 Hz, 6H).Found: [M+H]=212.2 (M−OH+MeO).

4-(Bromomethyl)-2-isopropoxy-6-methoxypyridine (149)

A solution of 148 (5.86 g, 29.9 mmol) in DCM (100 mL, anhydrous) at 0°C. was treated with triethylamine (8.3 mL, 59.5 mmol) and then mesylchloride (3.47 mL, 44.8 mmol), the mixture was stirred at 0° C. for 1 hthen partitioned between DCM and water. The organic fraction was driedand evaporated and the residue was dissolved in acetone (200 mL), LiBr(25.9 g, 299 mmol) was added and the mixture was refluxed for 1 h thenevaporated. The residue was partitioned between DCM and water; theorganic fraction was dried and evaporated. Column chromatography (DCM)gave 149 (6.98 g, 90%). ¹H NMR (CDCl₃) δ 6.28 (s, 1H), 6.27 (s, 1H),5.23 (sp, J=6.2 Hz, 1H), 4.27 (s, 2H), 3.88 (s, 3H), 1.35 (d, J=6.3 Hz,6H). Found: [M+H]=260.1.

6-Bromo-3-((2-isopropoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline(150)

A mixture of 1 (7.45 g, 26.4 mmol), 149 (6.84 g, 26.4 mmol) and Cs₂CO₃(17.3 g, 52.7 mmol) in toluene (100 mL) and DMF (50 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.61 g, 0.528 mmol) was added, the mixture waspurged with nitrogen and then heated to 80° C. under nitrogen for 3 h.The reaction mixture was partitioned between EtOAc and water and theorganic fraction was dried and evaporated. Column chromatography with3:1 hexanes:DCM eluted impurities, then elution with 1:1 hexanes:DCMgave 150 (8.59 g, 78%). ¹H NMR (CDCl₃) δ 7.78 (d, J=2.1 Hz, 1H), 7.69(d, J=8.9 Hz, 1H), 7.62 (dd, J=8.9, 2.2 Hz, 1H), 7.58 (s, 1H), 6.14 (d,J=0.9 Hz, 1H), 6.10 (d, J=0.9 Hz, 1H), 5.22 (sp, J=6.2 Hz, 1H), 4.06 (s,3H), 3.90 (s, 2H), 3.87 (s, 3H), 1.33 (d, J=6.2 Hz, 6H). Found:[M+H]=417.1.

(2-Ethoxy-6-methoxypyridin-4-yl)methanol (151)

Trimethylborate (6.06 mL, 53.1 mmol) and then borane-dimethylsulfide(5.04 mL, 53.1 mmol) were added to a solution of 145 (5.24 g, 26.6 mmol)in THF (100 mL, dist. Na) at 0° C. and the mixture was stirred at r.t.for 18 hr. The solution was cooled to 0° C. and quenched with methanol.Removal of the solvent gave a solid which was partitioned between EtOAcand water, the organic fraction was dried and evaporated to give 151(4.79 g, 98%). ¹H NMR (CDCl₃) δ 6.29 (bd, J=0.7 Hz, 1H), 6.28 (bd, J=0.7Hz, 1H), 4.63 (d, J=6.2 Hz, 2H), 4.32 (q, J=7.1 Hz, 2H), 3.90 (s, 3H),1.76 (t, J=6.2 Hz, 1H), 1.39 (t, J=7.1 Hz, 3H). Found: [M+H]⁼184.2.

4-(Bromomethyl)-2-ethoxy-6-methoxypyridine (152)

A solution of 151 (4.72 g, 25.9 mmol) in DCM (100 mL, anhydrous) at 0°C. was treated sequentially with triethylamine (7.22 mL, 51.8 mmol) andmesyl chloride (3.00 mL, 38.8 mmol), the mixture was stirred at 0° C.for 1 h then partitioned between DCM and water. The organic fraction wasdried and evaporated and the residue was dissolved in acetone (200 mL),LiBr (22.5 g, 259 mmol) was added and the mixture was refluxed for 1 hthen evaporated. The residue was partitioned between DCM and water; theorganic fraction was dried and evaporated. Column chromatography (DCM)gave 152 (5.78 g, 91%). ¹H NMR (CDCl₃) δ 6.30 (s, 2H), 4.33 (q, J=7.1Hz, 2H), 4.28 (s, 2H), 3.90 (s, 3H), 1.39 (t, J=7.1 Hz, 3H). Found:[M+H]=246.0.

6-Bromo-3-((2-ethoxy-6-methoxypyridin-4-yl)methyl)-2-methoxyquinoline(153)

A mixture of 1 (6.61 g, 23.4 mmol), 152 (5.77 g, 23.4 mmol) and Cs₂CO₃(15.25 g, 46.5 mmol) in toluene (100 mL) and DMF (50 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.54 g, 0.465 mmol) was added, the mixture waspurged with nitrogen then heated to 80° C. under nitrogen for 3 h. Thereaction mixture was partitioned between EtOAc and water and the organicfraction was dried and evaporated. Column chromatography with 3:1hexanes:DCM eluted impurities, then elution with 1:1 hexanes:DCM gave153 (6.69 g, 71%). ¹H NMR (CDCl₃) δ 7.78 (d, J=2.1 Hz, 1H), 7.69 (d,J=8.9 Hz, 1H), 7.63 (dd, J=8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.15 (d,J=8.0 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 4.06 (s, 3H), 3.91 (s, 2H), 3.88(s, 3H), 1.37 (t, J=7.1 Hz, 3H). Found: [M+H]=403.1.

Ethyl 2-ethoxy-6-hydroxyisonicotinate (154)

A suspension of 2,6-dihydroxyisonicotinic acid (40.00 g, 258 mmol) inEtOH (300 mL) was treated dropwise with H₂SO₄ (40 mL, 18.4 M, 752 mmol).The solution was refluxed for 72 h then evaporated; the residue wastreated with sat. aq. NaHCO₃ to pH 8 and then extracted with EtOAc(3×500 mL). The organic extracts were washed with sat. aq. NaHCO₃,brine, then dried and evaporated to give 154 (10.86 g, 20%). ¹H NMR(DMSO-d₆) δ 11.15 (bs, 1H), 6.59 (d, J=1.0 Hz, 1H), 6.57 (bs, 1H), 4.29(q, J=7.1 Hz, 2H), 4.25 (q, J=7.1 Hz, 2H), 1.298 (t, J=7.1 Hz, 3H),1.296 (t, J=7.1 Hz, 3H). Found: [M+H]=212.2.

Ethyl 2-ethoxy-6-isopropoxyisonicotinate (155)

A solution of 154 (10.82 g, 51.2 mmol) in DMF (125 mL, anhydrous) wastreated with K₂CO₃ (8.65 g, 62.5 mmol) and then 2-iodopropane (6.4 mL,64 mmol). The mixture was stirred at r.t. for 48 h, K₂CO₃ (8.65 g, 62.5mmol) and 2-iodopropane (6.4 mL, 64 mmol) were added and the mixture wasstirred for a further 24 h, partitioned between EtOAc and water and theaqueous layer was extracted with EtOAc. The organic fractions werewashed with water, dried and evaporated. Chromatography (DCM) gave 155(11.56 g, 89%). ¹H NMR (DMSO-d₆) δ 6.81 (s, 2H), 5.23 (sp, J=6.2 Hz,1H), 4.20-4.38 (m, 4H), 1.35-1.42 (m, 12H). Found: [M+H]=254.1.

2-Ethoxy-6-isopropoxyisonicotinic acid (156)

A solution of LiOH (3.25 g, 136 mmol) in water (60 mL) was added to asolution of 155 (11.42 g, 45.1 mmol) in THF (60 mL) and MeOH (60 mL),the solution was stirred at r.t. for 18 h and then evaporated. Theresidue was dissolved in water (150 mL) and acidified to pH 3 with 2 MHCl. The precipitate was filtered and dried to give 156 (10.03 g, 99%).¹H NMR (DMSO-d₆) δ 13.48 (bs, 1H), 6.66 (d, J=0.9 Hz, 1H), 6.64 (d,J=0.9 Hz, 1H), 5.17 (sp, J=6.2 Hz, 1H), 4.29 (q, J=7.0 Hz, 2H), 1.32 (t,J=7.0 Hz, 3H), 1.30 (d, J=6.2 Hz, 6H). Found: [M+H]=226.1.

2-Ethoxy-6-isopropoxy-N-methoxy-N-methylisonicotinamide (157)

Oxalyl chloride (3.13 mL, 37 mmol) was added to 156 (6.95 g, 30.8 mmol)in DCM (100 mL, anhydrous) and DMF (5.2 mmol) at r.t. The mixture wasstirred at r.t. for 1 h to give a colourless solution which was cooledto 0° C. N,O-Dimethylhydroxylamine hydrochloride (3.61 g, 37.0 mmol) andpyridine (7.5 mL, 92.7 mmol) were added sequentially and the mixture wasstirred at r.t. for 18 h, then partitioned between EtOAc and water. Theorganic fractions were washed with water, dried and evaporated. Columnchromatography with 95:5 DCM:EtOAc gave 157 (7.98 g, 97%). ¹H NMR(CDCl₃) δ 6.40 (s, 1H), 6.39 (s, 1H), 5.22 (sp, J=6.2 Hz, 1H), 4.33 (q,J=7.1 Hz, 2H), 3.60 (bs, 3H), 3.31 (s, 3H), 1.39 (t, J=6.2 Hz, 3H), 1.34(d, J=7.1 Hz, 6H). Found: [M+H]=269.2.

3-(Dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)propan-1-one(158)

Vinylmagnesium bromide (40 mL, 1 M in THF, 40 mmol) was added to asolution of 157 (5.33 g, 19.9 mmol) in THF (100 mL, dist. Na) at 0° C.,the brown solution was stirred at 0° C. for 1 h and then dimethylamine(40 mL, 2 M in THF, 80 mmol) and water (40 mL) were added. The solutionwas stirred at r.t. for 1 h then partitioned between EtOAc and water.The solution was dried and evaporated, to give 158 (5.57 g, 100%) as abrown oil. ¹H NMR (CDCl₃) δ 6.68 (d, J=1.0 Hz, 1H), 6.67 (d, J=1.0 Hz,1H), 5.22 (sp, J=6.2 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 3.05 (t, J=7.5 Hz,2H), 2.72 (t, J=7.5 Hz, 2H), 2.26 (s, 6H), 1.40 (t, J=6.2 Hz, 3H), 1.36(d, J=7.0 Hz, 6H). Found: [M+H]=281.7.

Methyl 2-methoxy-6-propoxyisonicotinate (159)

A solution of 139 (6.00 g, 32.8 mmol) in DMF (100 mL, anhydrous) wastreated with K₂CO₃ (6.80 g, 49.2 mmol) and then 1-iodopropane (4.8 mL,49.2 mmol). The mixture was stirred at r.t. for 48 h, partitionedbetween EtOAc and water and the aqueous layer was extracted with EtOAc.The organic fractions were washed with water, dried and evaporated.Column chromatography (DCM) gave 159 (6.59 g, 89%). ¹H NMR (CDCl₃) δ6.85 (d, J=1.0 Hz, 1H), 6.83 (d, J=1.0 Hz, 1H), 4.24 (t, J=6.7 Hz, 2H),3.93 (s, 3H), 3.91 (s, 3H), 1.80 (qt, J=7.4, 6.7 Hz, 2H), 1.02 (t, J=7.4Hz, 3H). Found: [M+H]=226.1.

2-Methoxy-6-propoxyisonicotinic acid (160)

A solution of LiOH (2.04 g, 85.2 mmol) in water (60 mL) was added to asolution of 159 (6.40 g, 28.4 mmol) in THF (60 mL) and MeOH (60 mL), thesolution was stirred at r.t. for 18 h and then evaporated. The residuewas dissolved in water (200 mL) and acidified to pH 3 with 2 M HCl. Theprecipitate was filtered and dried to give 160 (5.39 g, 90%). ¹H NMR(DMSO-d₆) δ 13.53 (bs, 1H), 6.73 (d, J=1.0 Hz, 1H), 6.72 (d, J=1.0 Hz,1H), 4.23 (t, J=6.6 Hz, 2H), 3.87 (s, 3H), 1.73 (qt, J=7.4, 6.6 Hz, 2H),0.96 (t, J=7.4 Hz, 3H). Found: [M+H]=212.1.

(2-Methoxy-6-propoxypyridin-4-yl)methanol (161)

Trimethylborate (5.8 mL, 50.8 mmol) and borane dimethylsulfide complex(4.8 mL, 50.6 mmol) were added sequentially to a solution of 160 (5.39g, 25.5 mmol) in THF (100 mL, dist. Na) at 0° C., and the mixture wasstirred at r.t. for 16 hr. The solution was cooled to 0° C. and methanolwas cautiously added o quench the reaction. Removal of the solvent gavea solid which was partitioned between EtOAc and water, the organicfraction was dried and evaporated. Column chromatography (3:1hexanes:EtOAc) gave 161 (5.04 g, 100%). ¹H NMR (CDCl₃) δ 6.28 (d, J=0.8Hz, 1H), 6.26 (d, J=0.8 Hz, 1H), 4.62 (d, J=6.2 Hz, 2H), 4.31 (q, J=7.1Hz, 2H), 4.20 (t, J=6.8 Hz, 2H), 1.72-1.83 (m, 3H), 1.38 (t, J=7.0 Hz,3H), 1.00 (t, J=7.4 Hz, 3H). Found: [M+H]=198.2.

4-(Bromomethyl)-2-methoxy-6-propoxypyridine (162)

A solution of 161 (5.00 g, 25.4 mmol) in DCM (100 mL, anhydrous) at 0°C. was treated with triethylamine (7.07 mL, 50.7 mmol) and then mesylchloride (2.94 mL, 38.0 mmol), the mixture was stirred at 0° C. for 1 hthen partitioned between DCM and water. The organic fraction was driedand evaporated and the residue was dissolved in acetone (150 mL), LiBr(22.0 g, 253 mmol) was added and the mixture was refluxed for 1 h thenevaporated. The residue was partitioned between DCM and water; theorganic fraction was dried and evaporated. Column chromatography (DCM)gave 162 (6.15 g, 93%) as a colourless oil. ¹H NMR (CDCl₃) δ 6.31 (d,J=1.0 Hz, 1H), 6.30 (d, J=1.0 Hz, 1H), 4.28 (s, 2H), 4.22 (t, J=6.7 Hz,2H), 3.90 (s, 3H), 1.79 (qt, J=7.4, 6.7 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H).Found: [M+H]=260.5.

6-Bromo-2-methoxy-3-((2-methoxy-6-propoxypyridin-4-yl)methyl)quinoline(163)

A mixture of 1 (6.62 g, 23.5 mmol), 162 (6.11 g, 23.5 mmol) and Cs₂CO₃(15.3 g, 47.0 mmol) in toluene (66 mL) and DMF (33 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.54 g, 0.47 mmol) was added, the mixture waspurged with nitrogen then heated to 80° C. under nitrogen for 3 h. Thereaction was partitioned between EtOAc and water and the organicfraction was dried and evaporated. Column chromatography with 1:1DCM:hexanes gave an impure product which was rechromatographed using agradient of 2:1 hexanes:DCM to 1:1 hexanes:DCM to give 163 (6.63 g,68%). ¹H NMR (CDCl₃) δ 7.78 (d, J=2.2 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H),7.63 (dd, J=8.9, 2.2 Hz, 1H), 7.58 (s, 1H), 6.15 (s, 1H), 6.14 (s, 1H),4.21 (t, J=6.8 Hz, 2H), 4.06 (s, 3H), 3.91 (s, 2H), 3.88 (s, 3H), 1.79(qt, J=7.4, 6.8 Hz, 2H), 1.00 (t, J=7.4 Hz, 3H). Found: [M+H]=417.1.

6-Chloro-2-methoxyquinoline (164)

A mixture of 2,6-dichloroquinoline (12.92 g, 65.3 mmol) and sodiummethoxide (17.63 g, 326 mmol) in MeOH (200 mL) was refluxed for 18 h.The solvent was removed in vacuo and the residue was partitioned betweenEtOAc and water. Recrystallisation from MeOH gave 164 (11.63 g, 92%). ¹HNMR (CDCl₃) δ 7.89 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.69 (d,J=2.3 Hz, 1H), 7.55 (dd, J=8.9, 2.4 Hz, 1H), 6.92 (d, J=8.9 Hz, 1H),4.06 (s, 3H). Found: [M+H]=194.0.

(6-Chloro-2-methoxyquinolin-3-yl)1 (165)

A solution of anhydrous 2,2,6,6,-tetramethylpiperidine (6.7 mL, 39.7mmol) in THF (70 mL, dist. Na) at −40° C. was treated with n-BuLi (19.8mL, 2 M in cyclohexane, 39.7 mmol), the solution was then stirred at−40° C. for 5 min and then cooled to −78° C. A solution of 164 (6.35 g,32.9 mmol) and triisopropylborate (9.1 mL, 39.7 mmol) in THF (50 mL,dist. Na) was added dropwise and the orange solution was stirred for 3 hat −78° C., then quenched with sat. aq. NH₄Cl and ice. The precipitatewas filtered, triturated with hexanes and dried to give 165 (5.84 g,75%). ¹H NMR (DMSO-d₆) δ 8.35 (s, 1H), 8.17 (s, 2H), 8.02 (d, J=2.4 Hz,1H), 7.76 (d, J=8.9 Hz, 1H), 7.65 (dd, J=8.9, 2.5 Hz, 1H), 3.99 (s, 3H).Found: [M-OH+OMe]=252.2.

6-Chloro-3-(2-fluoro-3-methoxybenzyl)-2-methoxyquinoline (166)

A mixture of 165 (5.00 g, 21.1 mmol),1-(bromomethyl)-2-fluoro-3-methoxybenzene (4.61 g, 21.0 mmol) and Cs₂CO₃(13.7 g, 42.0 mmol) in toluene (100 mL) and DMF (50 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.49 g, 0.42 mmol) was added, the mixture waspurged with nitrogen then heated to 80° C. under nitrogen for 3 h. Thereaction was partitioned between EtOAc and water and the organicfraction was dried and evaporated. Column chromatography with 3:1hexanes:DCM eluted impurities, then elution with 1:1 hexanes:DCM gave166 (3.40 g, 57%). ¹H NMR (CDCl₃) δ 7.74 (d, J=8.8 Hz, 1H), 7.58 (d,J=2.4 Hz, 1H), 7.52 (s, 1H), 7.48 (dd, J=8.9, 2.4 Hz, 1H), 7.01 (td,J=8.0, 1.5 Hz, 1H), 6.88 (td, J=8.1, 1.5 Hz, 1H), 6.78 (td, J=7.0, 1.5Hz, 1H), 4.09 (s, 3H), 4.05 (s, 2H), 3.90 (s, 3H). Found: [M+H]=332.1.

N,2-Dimethoxy-N-methyl-6-propoxyisonicotinamide (167)

Oxalyl chloride (2.76 mL, 32.6 mmol) was added to 160 (5.74 g, 27.2mmol) in DCM (100 mL, anhydrous) and DMF (0.4 mL, 5.2 mmol) at r.t. Themixture was stirred at r.t. for 1 h to give a colourless solution whichwas cooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (3.18 g,32.6 mmol) and pyridine (6.6 mL, 81.6 mmol) were added sequentially andthe mixture was stirred at r.t. for 18 h, then partitioned between DCMand water. Column chromatography on alumina with DCM gave 167 (6.29 g,91%). ¹H NMR (CDCl₃) δ 6.42 (s, 1H), 6.41 (s, 1H), 5.24 (sp, J=6.2 Hz,1H), 3.90 (s, 3H), 3.59 (bs, 3H), 3.32 (s, 3H), 1.35 (d, J=6.2 Hz, 6H).Found: [M+H]=255.1.

3-(Dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)propan-1-one (168)

Vinylmagnesium bromide (43 mL, 1 M in THF, 43 mmol) was added to asolution of 167 (5.78 g, 21.7 mmol) in THF (100 mL, dist. Na) at 0° C.,the brown solution was stirred at 0° C. for 1 h and then dimethylamine(43 mL, 2 M in THF, 86 mmol) and water (40 mL) were added. The solutionwas stirred at r.t. for 1 h then partitioned between EtOAc and water.The solution was dried and evaporated to give 168 (5.75 g, 100%). ¹H NMR(CDCl₃) δ 6.73 (d, J=1.1 Hz, 1H), 6.72 (d, J=1.1 Hz, 1H), 4.26 (t, J=6.7Hz, 2H), 3.93 (s, 3H), 3.06 (t, J=7.4 Hz, 2H), 2.72 (J=7.4 Hz, 2H), 2.27(s, 6H), 1.80 (qt, J=7.4, 6.7 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). Found:[M+H]=267.2.

Benzofuran-7-ylmethanol (169)

A solution of methyl benzofuran-7-carboxylate (3.59 g, 20.4 mmol) inEt₂O (100 mL, dist. Na) at 0° C. was treated with LiAlH₄ (1.54 g, 40.6mmol) then stirred at r.t. for 3 h and quenched with ice. The mixturewas partitioned between Et₂O and sat. aq. sodium potassium tartrate andthen filtered through Celite. The aqueous layer was extracted with Et₂Oand the organic phases were combined and dried. Column chromatography(0-5% EtOAc:DCM) gave 169 (2.60 g, 86%). ¹H NMR (CDCl₃) δ 7.65 (d, J=2.2Hz, 1H), 7.56 (dd, J=7.7, 1.2 Hz, 1H), 7.31 (dd, J=7.3, 0.6 Hz, 1H),7.23 (t, J=7.5 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 5.02 (d, J=6.2 Hz, 2H),1.93 (t, J=6.2 Hz, 1H).

7-(Bromomethyl)benzofuran (170)

A solution of 169 (4.72 g, 31.8 mmol) in DCM (100 mL, anhydrous) at 0°C. was treated sequentially with triethylamine (8.9 mL, 63.9 mmol) thenmesyl chloride (3.70 mL, 47.8 mmol), the mixture was stirred at 0° C.for 1 h then partitioned between DCM and water. The organic fraction wasdried and evaporated and the residue was dissolved in acetone (200 mL),LiBr (27.6 g, 318 mmol) was added and the mixture was refluxed for 0.5 hand then evaporated. The residue was partitioned between DCM and water;the organic fraction was dried and evaporated. Column chromatography(DCM) gave 170 (6.08 g, 90%). ¹H NMR (CDCl₃) δ 7.69 (d, J=2.2 Hz, 1H),7.57 (dd, J=7.7, 1.2 Hz, 1H), 7.32 (dd, J=7.4, 0.7 Hz, 1H), 7.22 (t,J=7.6 Hz, 1H), 6.80 (d, J=2.2 Hz, 1H), 4.81 (s, 2H).

3-(Benzofuran-7-ylmethyl)-6-bromo-2-methoxyquinoline (171)

A mixture of 1 (8.00 g, 28.4 mmol), 170 (5.99 g, 28.4 mmol) and Cs₂CO₃(18.5 g, 56.7 mmol) in toluene (100 mL) and DMF (50 mL) was purged withnitrogen. Pd(PPh₃)₄ (0.66 g, 0.57 mmol) was added, the mixture waspurged with nitrogen then heated to 80° C. under nitrogen for 3 h. Thereaction was partitioned between EtOAc and water and the organicfraction was dried and evaporated. Column chromatography with 3:1hexanes:DCM eluted impurities, then elution with 1:1 hexanes:DCM thenDCM gave 171 (6.95 g, 67%). ¹H NMR (CDCl₃) δ 7.71 (d, J=2.2 Hz, 1H),7.68 (d, J=8.8 Hz, 1H), 7.58-7.62 (m, 2H), 7.50-7.54 (m, 2H), 7.20 (t,J=7.4 Hz, 1H), 7.13 (dd, J=7.4, 0.6 Hz, 1H), 6.79 (d, J=2.2 Hz, 1H),4.32 (s, 2H), 4.10 (s, 3H). Found: [M+H]=368.8.

Methyl 2-cyclobutoxy-6-methoxyisonicotinate (172)

A solution of 139 (3.00 g, 16.4 mmol) in DMF (50 mL, anhydrous) wastreated with K₂CO₃ (4.52 g, 32.7 mmol) and then bromocyclobutane (2.00mL, 25.0 mmol). The mixture was stirred at r.t. for 48 h, partitionedbetween EtOAc and water and the aqueous layer was extracted with EtOAc.The organic fractions were washed with water, dried and evaporated.Column chromatography (DCM) gave 172 (2.21 g, 57%). ¹H NMR (CDCl₃) δ6.84 (d, J=1.0 Hz, 1H), 6.79 (d, J=1.0 Hz, 1H), 5.08 (pd, J=7.4, 0.8 Hz,1H), 3.91 (s, 3H), 3.90 (s, 3H), 2.42-2.52 (m, 2H), 2.12-2.24 (m, 2H),1.80-1.90 (m, 1H), 1.62-1.75 (m, 1H). Found: [M+H]=238.2.

2-Cyclobutoxy-6-methoxyisonicotinic acid (173)

A solution of LiOH (0.71 g, 29.6 mmol) in water (20 mL) was added to asolution of 172 (2.20 g, 9.29 mmol) in MeOH (20 mL) and THF (20 mL); thesolution was stirred at r.t. for 18 h and then evaporated. The residuewas dissolved in water (80 mL) and acidified to pH 3 with 2 M HCl. Theprecipitate was filtered and dried to give 173 (2.02 g, 97%). ¹H NMR(DMSO-d₆) δ 13.56 (bs, 1H), 6.74 (d, J=1.0 Hz, 1H), 6.67 (d, J=1.0 Hz,1H), 5.07 (pd, J=7.1, 0.7 Hz, 1H), 3.85 (s, 3H), 2.37-2.46 (m, 2H),2.14-2.22 (m, 2H), 1.74-1.83 (m, 1H), 1.59-1.72 (m, 1H). Found:[M+H]=224.2.

2-Cyclobutoxy-N,6-dimethoxy-N-methylisonicotinamide (174)

Oxalyl chloride (0.45 mL, 5.32 mmol) was added to a suspension of 173(1.00 g, 4.48 mmol) in DCM (50 mL, anhydrous) and DMF (0.2 mL) at r.t.The mixture was stirred at r.t. for 1 h to give a colourless solutionwhich was cooled to 0° C. N,O-Dimethylhydroxylamine hydrochloride (0.52g, 5.33 mmol) and pyridine (1.09 mL, 13.5 mmol) were added sequentiallyand the mixture was stirred at r.t. for 18 h, then partitioned betweenDCM and sat. aq. NaHCO₃. Column chromatography on alumina with DCM gave174 (1.01 g, 85%). ¹H NMR (CDCl₃) δ 6.46 (s, 1H), 6.40 (d, J=0.6 Hz,1H), 5.08 (pd, J=7.4, 0.9 Hz, 1H), 3.90 (s, 3H), 3.58 (bs, 3H), 3.32 (s,3H), 2.41-2.51 (m, 2H), 2.12-2.23 (m, 2H), 1.80-1.90 (m, 1H), 1.62-1.74(m, 1H). Found: [M+H]=267.2.

1-(2-cyclobutoxy-6-methoxypyridin-4-yl)-3-(dimethylamino)propan-1-one(175)

Vinylmagnesium bromide (8.0 mL, 1 M, 8.0 mmol) was added to a solutionof 174 (1.02 g, 3.84 mmol) in THF (50 mL, dist. Na) at 0° C., the brownsolution was warmed to r.t. for 1 h then dimethylamine in THF (8.0 mL,2M, 16.0 mmol) and water (10 mL) were added. The solution was stirred atr.t. for 1 h, and then partitioned between EtOAc and water. The solutionwas dried and evaporated, column chromatography (95:5 DCM:MeOH) gave 175(1.05 g, 97%). ¹HNMR (CDCl₃) δ 6.73 (d, J=1.1 Hz, 1H), 6.68 (d, J=1.2Hz, 1H), 5.10 (pd, J=7.4, 1.1 Hz, 1H), 3.91 (s, 3H), 3.05 (t, J=7.0 Hz,2H), 2.72 (t, J=7.0 Hz, 2H), 2.42-2.50 (m, 2H), 2.27 (s, 6H), 2.13-2.23(m, 2H), 1.80-1.90 (m, 1H), 1.62-1.74 (m, 1H). Found: [M+H]=279.2.

(2-Ethoxy-6-isopropoxypyridin-4-yl)methanol (176)

Trimethylborate (3.03 mL, 26.7 mmol) and then borane-dimethylsulfide(2.53 mL, 26.7 mmol) were added to a solution of 156 (3.00 g, 13.3 mmol)in THF (50 mL, dist. Na) at 0° C. and the mixture was stirred at r.t.for 18 hr. The solution was cooled to 0° C. and methanol was cautiouslyadded to quench the reaction. Removal of the solvent gave a solid, thiswas partitioned between EtOAc and water, the organic fraction was driedand evaporated. Column chromatography (3:1 hexanes:EtOAc) gave 176 (2.72g, 97%). ¹H NMR (CDCl₃) δ 6.24 (s, 1H), 6.23 (s, 1H), 5.21 (sp, J=6.2Hz, 1H), 4.60 (d, J=6.2 Hz, 2H), 4.30 (q, J=7.0 Hz, 2H), 1.70 (t, J=6.2Hz, 1H), 1.38 (t, J=7.0 Hz, 3H), 1.34 (d, J=6.2 Hz, 6H). Found:[M+H]=212.2.

4-(Bromomethyl)-2-ethoxy-6-isopropoxypyridine (177)

A solution of 176 (2.60 g, 12.3 mmol) in DCM (50 mL, anhydrous) at 0° C.was treated sequentially with triethylamine (3.43 mL, 24.6 mmol) thenmesyl chloride (1.43 mL, 18.5 mmol), the mixture was stirred at 0° C.for 1 h then partitioned between DCM and water. The organic fraction wasdried and evaporated and the residue was dissolved in acetone (100 mL),LiBr (10.7 g, 123 mmol) was added and the mixture was refluxed for 1 hand then evaporated. The residue was partitioned between DCM and water;the organic fraction was dried and evaporated. Column chromatography(DCM) gave 177 (3.04 g, 100%). ¹H NMR (CDCl₃) δ 6.26 (s, 1H), 6.25 (s,1H), 5.20 (sp, J=6.2 Hz, 1H), 4.26-4.33 (m, 4H), 1.38 (t, J=7.0 Hz, 3H),1.34 (d, J=6.2 Hz, 6H). Found: [M+H]=274.1.

6-Bromo-3-((2-ethoxy-6-isopropoxypyridin-4-yl)methyl)-2-methoxyquinoline(178)

A mixture of 1 (11.6 mmol), 177 (3.18 g, 11.6 mmol) and Cs₂CO₃ (7.56 g,23.2 mmol) in toluene (66 mL) and DMF (33 mL) was purged with nitrogen.Pd(PPh₃)₄ (0.27 g, 0.23 mmol) was added, the mixture was purged withnitrogen then heated to 80° C. under nitrogen for 3 h. The reaction waspartitioned between EtOAc and water and the organic fraction was driedand evaporated. Column chromatography with 3:1 hexanes:DCM elutedimpurities, then elution with DCM gave 178 (3.42 g, 68%) as white solid.¹H NMR (CDCl₃) δ 7.77 (d, J=2.1 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.62(dd, J=8.8, 2.2 Hz, 1H), 7.58 (s, 1H), 6.11 (s, 1H), 6.10 (s, 1H), 5.20(sp, J=6.2 Hz, 1H), 4.28 (q, J=7.1 Hz, 2H), 4.06 (s, 3H), 3.89 (s, 2H),1.36 (t, J=7.1 Hz, 3H), 1.32 (d, J=6.2 Hz, 6H). Found: [M+H]=431.1.

(6-Chloro-2-methoxyquinolin-3-yl)(m-tolyl)methanol (179)

n-BuLi (12.4 mL, 2 M in cyclohexanes, 24.8 mmol) was added to a solutionof 2,2,6,6,-tetramethylpiperidine (4.18 mL, 24.8 mmol) in THF (50 mL,dist. Na) at −40° C. and the solution was stirred for 5 min then cooledto −78° C. A solution of 164 (4.00 g, 20.7 mmol) in THF (40 mL, dist.Na) was added and the solution was stirred at −78 for 1.5 h, then asolution of m-tolualdehyde (2.49 g, 20.7 mmol) in THF (10 mL, dist, Na)was added. The solution was stirred at −78° C. for 3 h then acetic acid(3.55 mL, 62.0 mmol) was added, the mixture was partitioned betweenEtOAc and water and the aqueous was extracted with EtOAc, the organicfractions were combined and evaporated. Column chromatography (3:1hexanes:DCM to 2:1 hexanes:DCM to DCM and then 95:5 DCM:EtOAc) gave 179(3.39 g, 55%) as a white solid. ¹H NMR (CDCl₃) δ 7.88 (s, 1H), 7.76 (d,J=8.9 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.53 (dd, J=8.9, 2.4 Hz, 1H),7.16-7.25 (m, 2H), 7.11 (d, J=7.4 Hz, 1H), 6.03 (d, J=3.8 Hz, 1H), 4.05(s, 3H), 2.86 (d, J=4.3 Hz, 1H), 2.34 (s, 3H). Found: [M+H]=314.1.

6-Chloro-2-methoxy-3-(3-methylbenzyl)quinoline (180)

A solution of 179 (3.36 g, 11.3 mmol) in DCM (60 mL) was treated withtrifluoroacetic acid (8.4 mL, 113 mmol) and then triethylsilane (14.5mL, 89.9 mmol). The solution was refluxed for 18 h, neutralised withsat. aq. NaHCO₃ and partitioned with water. The organic phase was driedand evaporated, column chromatography (3:1 hexanes:DCM) gave 180 (2.27g, 67%). ¹H NMR (CDCl₃) δ 7.75 (d, J=8.9 Hz, 1H), 7.58 (d, J=2.4 Hz,1H), 7.46-7.50 (m, 2H), 7.21 (t, J=7.8 Hz, 1H), 7.01-7.08 (m, 3H), 4.08(s, 3H), 3.99 (s, 2H), 2.33 (s, 3H). Found: [M+H]=298.1.

(2,6-Dimethoxypyridin-4-yl)methanol (279)

Borane-dimethylsulfide (4.60 mL, 48.5 mmol) and trimethylborate (5.58mL, 49.1 mmol) were added to a solution of 2,6-dimethoxyisonicotinicacid (3.00 g, 16.4 mmol) in THF (100 mL, dist. Na) at 0° C., thesolution was then stirred at r.t. for 18 h, cooled to 0° C., quenchedwith MeOH and evaporated. The residue was partitioned between EtOAc andwater and the organic fraction was dried and evaporated. Columnchromatography (2:1 hexanes:EtOAc) gave 279 (2.72 g, 98%). ¹HNMR (CDCl₃)δ 6.30 (s, 2H), 4.64 (d, J=5.8 Hz, 2H), 3.91 (s, 6H), 1.75 (t, J=6.1 Hz,1H). Found: [M+H]=170.1.

4-(Bromomethyl)-2,6-dimethoxypyridine (280)

A solution of 279 (1.57 g, 9.30 mmol) in DCM (40 mL, anhydrous) at 0° C.was treated with triethylamine (2.60 mL, 18.6 mmol) then mesyl chloride(1.08 mL, 13.9 mmol), the mixture was stirred at 0° C. for 1 h thenpartitioned between DCM and water. The organic fraction was dried andevaporated and the residue was dissolved in acetone (50 mL). LiBr (4.04g, 46.5 mmol) was added and the mixture was refluxed for 1 h thenevaporated. The residue was partitioned between DCM and water and theorganic fraction was dried and evaporated. Column chromatography (DCM)gave 280 (1.96 g, 91%). ¹H NMR (CDCl₃) δ 6.32 (s, 2H), 4.29 (s, 2H),3.91 (s, 6H). Found: [M+H]=232.0.

6-Bromo-3-((2,6-dimethoxypyridin-4-yl)methyl)-2-methoxyquinoline (281)

A mixture of 1 (2.20 g, 7.80 mmol), 280 (1.93 g, 8.30 mmol), Cs₂CO₃(5.10 g, 15.7 mmol) and Pd(PPh₃)₄ (0.45 g, 0.39 mmol) in DMF (10 mL) andtoluene (20 mL) was purged with nitrogen, then heated to 80° C. for 4 hunder nitrogen. The mixture was partitioned between EtOAc and water andthe organic fraction was dried and evaporated. Column chromatography(3:1 hexanes:DCM) eluted non polar impurities, elution with DCM gave 281(1.95 g, 64%). ¹H NMR (CDCl₃) δ 7.78 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 7.63 (dd, J=8.9, 2.2 Hz, 1H), 7.57 (s, 1H), 6.17 (s, 2H), 4.06(s, 3H), 3.92 (s, 2H), 3.89 (s, 6H). Found: [M+H]=389.1.

N-Methoxy-N,2,6-trimethylisonicotinamide (282)

Oxalyl chloride (1.46 mL, 17.3 mmol) was added to a suspension of2,6-dimethylisonicotinic acid (2.38 g, 15.7 mmol) in DCM (100 mL,anhydrous) and DMF (1.3 mmol) at r.t. The mixture was stirred at r.t.for 1 h to give a colorless solution which was cooled to 0° C.N,O-Dimethylhydroxylamine hydrochloride (1.46 mL, 17.3 mmol) andpyridine (3.82 mL, 47.2 mmol) were added sequentially and the mixturewas stirred at r.t. for 18 h, then partitioned between EtOAc and sat.aq. NaHCO₃. Column chromatography with hexanes:EtOAc 1:1 gave 282 as anoil (1.50 g, 49%). ¹H NMR (CDCl₃) δ 7.15 (s, 2H), 3.56 (s, 3H), 3.35 (s,3H), 2.57 (s, 6H). Found: [M+H]=195.1.

3-(Dimethylamino)-1-(2,6-dimethylpyridin-4-yl)propan-1-one (283)

Vinylmagnesium bromide solution in THF (1N, 22.0 mL, 22 mmol) was addedto a solution of 282 (1.43 g, 7.37 mmol) in THF (100 mL, dist. Na) at 0°C., the brown solution was warmed to r.t. for 1 h then dimethylamine inTHF (2N, 22.0 mL, 44 mmol) and water (20 mL) were added. The solutionwas stirred at r.t. for 1 h, then partitioned between EtOAc and water.The solution was dried and evaporated to give 283 as a yellow oil (1.54g, 99%). ¹H NMR (CDCl₃) δ 7.38 (s, 2H), 3.10 (t, J=7.2 Hz, 2H), 2.74 (t,J=7.2 Hz, 2H), 2.61 (s, 6H), 2.28 (s, 6H). Found: [M+H]=207.2.

II. Preparation of Representative Embodiments of the Invention Example 11-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol(181)

General Coupling Procedure:

n-BuLi (2.63 mL of a 2N solution in cyclohexane, 5.26 mmol) was added at−30° C. under dry nitrogen to a solution of dry diisopropylamine (0.74mL, 5.26 mmol) in dry THF (6 mL) and the solution was stirred at thistemperature for 10 min, then cooled to −78° C. A solution of 10 (1.50 g,4.38 mmol) in dry THF (6 mL) was added dropwise and the mixture wasstirred at −78° C. for 90 min, to give a dark, wine-red coloredsolution. A solution of dry 6 (1.15 g, 4.82 mmol) in dry THF (7 mL) wasadded and the reaction mixture was stirred at this temperature for 4 h.HOAc (0.90 mL) was added and the reaction mixture was warmed to r.t.Water (100 mL) was added and the mixture was extracted with EtOAc (2×).The combined organic extract was washed with sat. aq. NaHCO₃ solution,and brine, then dried (Na₂SO₄) and the solvent removed under reducedpressure. The residue was purified by flash column chromatography.Elution with 0-10% MeOH/DCM gave fore fractions of unreacted 10,followed by the product 181 as a 1:1 mixture of diastereomers (0.91 g,36%). Found: [M+H]=580.1.

The following compounds were synthesised using the General CouplingProcedure. Each coupled product was resolved into its four opticalisomers using preparative chiral HPLC.

Example 22-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol(182)

From coupling of 3-benzyl-6-bromo-2-methoxyquinoline and (114). Columnchromatography of the crude product with 0-5% MeOH:DCM gave forefractions, followed by 182. Found: [M+H]=544.9.

Example 31-(6-Bromo-2-methoxyquinolin-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)butan-2-ol(183)

From coupling of 117 and3-(dimethylamino)-1-(3-fluorophenyl)propan-1-one. Column chromatographyof the crude product with 0-5% MeOH:DCM gave fore fractions, followed by183. Found: [M+H]=583.9.

Example 41-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(m-tolyl)butan-2-ol(184)

From coupling of 120 and 3-(dimethylamino)-1-(m-tolyl)propan-1-one.Column chromatography of the crude product with 0-5% MeOH:DCM gave forefractions, followed by 184. Found: [M+H]=580.0.

Example 51-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(185)

From coupling of 8 and 4. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 185. Found:[M+H]=642.1.

Example 62-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol(186)

From coupling of 9 and 122. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 186. Found:[M+H]=562.9.

Example 72-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(187)

From coupling of 120 and 122. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 187. Found:[M+H]=606.1.

Example 82-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol(188)

From coupling of 9 and 114. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 188. Found:[M+H]=562.9.

Example 91-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(189)

From coupling of 120 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 189. Found:[M+H]=627.1.

Example 102-(Benzofuran-5-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(190)

From coupling of 120 and 126. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 190. Found:[M+H]=606.1.

Example 111-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-methylthiophen-2-yl)butan-2-ol(191)

From coupling of 16 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 191. Found:[M+H]=586.1.

Example 122-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(192)

From coupling of 129 and 114. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 192. Found:[M+H]=634.2.

Example 131-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(193)

From coupling of 8 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 193. Found:[M+H]=614.0.

Example 142-(Benzofuran-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol(194)

From coupling of 3-benzyl-6-bromo-2-methoxyquinoline and 134. Columnchromatography of the crude product with 0-5% MeOH:DCM gave forefractions, followed by 194. Found: [M+H]=544.5.

Example 152-(Benzo[b]thiophen-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol(195)

From coupling of 3-benzyl-6-bromo-2-methoxyquinoline and 138. Columnchromatography of the crude product with 0-5% MeOH:DCM gave forefractions, followed by 195. Found: [M+H]=561.0.

Example 161-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol(196)

From coupling of 8 and 143. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 196. Found:[M+H]=642.1.

Example 171-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(197)

From coupling of 8 and 147. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 197. Found:[M+H]=627.7.

Example 181-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol(198)

From coupling of 120 and 143. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 198. Found:[M+H]=655.1.

Example 191-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol(199)

From coupling of 150 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 199. Found:[M+H]=655.0.

Example 201-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)butan-2-ol(200)

From coupling of 120 and 147. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 200. Found:[M+H]=641.2.

Example 212-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol(201)

From coupling of 150 and 114. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 2012 Found:[M+H]=634.1.

Example 222-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)butan-2-ol(202)

From coupling of 153 and 114. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 202. Found:[M+H]=620.1.

Example 231-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol(203)

From coupling of 120 and 158. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 203. Found:[M+H]=669.0.

Example 241-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol(204)

From coupling of 281 and 158. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 204. Found:[M+H]=669.0.

Example 251-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)-1-(m-tolyl)butan-2-ol(205)

From coupling of 10 and 143. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 205. Found:[M+H]=607.7.

Example 261-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)butan-2-ol(206)

From coupling of 163 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 206. Found:[M+H]=654.7.

Example 271-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(207)

From coupling of 166 and 4. Column chromatography of the crude productwith 0-3% MeOH:DCM gave fore fractions, followed by 207. Found:[M+H]=597.8.

Example 281-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy-6-propoxypyridin-4-yl)butan-2-ol(208)

From coupling of 120 and 168. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 208. Found:[M+H]=654.7.

Example 291-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(209)

From coupling of 171 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 209. Found:[M+H]=605.7.

Example 301-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(210)

From coupling of 120 and 175. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 210. Found:[M+H]=666.7.

Example 311-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol(211)

From coupling of 178 and 6. Column chromatography of the crude productwith 0-5% MeOH:DCM gave fore fractions, followed by 211. Found:[M+H]=669.0.

Example 321-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol(212)

From coupling of 180 and 4. Column chromatography of the crude productwith 0-3% MeOH:DCM gave fore fractions, followed by 212. Found:[M+H]=564.0.

Example 331-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5-dimethylthiophen-3-yl)butan-2-ol(213)

From coupling of 14 and 6. Column chromatography with EtOAc:hexanes(1:3) eluted unreacted 14 while hexanes:EtOAc (1:1) gave 213. Found:[M+H]=600.1.

Example 341-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol(214)

From coupling of 10 and 4. Column chromatography with EtOAc:hexanes(1:9) gave fore fractions, then elution with EtOAc:hexanes (1:4) gave214. Found: [M+H]=608.2.

Example 351-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)butan-2-ol(215)

From coupling of 11 and 4. Column chromatography with EtOAc:hexanes(1:9) gave fore fractions, then elution with EtOAc:hexanes (1:1) gave215. Found: [M+H]=654.1.

Example 361-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(216)

From coupling of 120 and 4. Column chromatography with EtOAc:hexanes(1:4), then EtOAc gave fore fractions, followed by 216. Found:[M+H]=655.1.

Example 371-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)butan-2-ol(217)

From coupling of 11 and 283. Column chromatography with MeOH:DCM (0-8%)gave fore fractions, then 217. Found: [M+H]=594.1.

Example 381-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxypyridin-3-yl)butan-2-ol(218)

From coupling of 17 and 6. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave fore fractions, followed by 218. Found:[M+H]=597.1.

Example 391-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol(219)

From coupling of 9 and 6. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave 219. Found: [M+H]=584.1.

Example 401-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamino)-1-phenylbutan-2-ol(220)

From coupling of 3-benzyl-6-bromo-2-methoxyquinoline and 19. Columnchromatography with EtOAc:hexanes (1:1) gave fore fractions, then 220.Found: [M+H]=545.3.

Example 411-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(221)

From coupling of 22 and 6. Column chromatography with EtOAc:hexanes(1:1) gave fore fractions, then 221. Found: [M+H]=624.1.

Example 422-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinolin-3-yl)-1-phenylbutan-2-ol(222)

From coupling of 23 and 6. Column chromatography with EtOAc:hexanes(3:7) gave fore fractions, then 222. Found: [M+H]=614.1.

Example 431-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol(223)

From coupling of 22 and 4. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave 223. Found: [M+H]=652.2.

Example 442-(2,6-Bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(224)

From coupling of 8 and 26. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave 224. Found: [M+H]=674.1.

Example 452-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(225)

From coupling of 8 and 29. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave fore fractions, followed by 225. Found:[M+H]=646.0.

Example 462-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(226)

From coupling of 120 and 29. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave fore fractions, followed by 226. Found:[M+H]=659.1.

Example 471-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol(227)

From coupling of 30 and 4. Column chromatography with EtOAc:hexanes(1:1) gave fore fractions, then 227. Found: [M+H]=626.1.

Example 481-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butan-2-ol(228)

From coupling of 8 and 33. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave fore fractions, followed by 228. Found:[M+H]=630.0.

Example 491-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol(229)

From coupling of 8 and 37. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave 229. Found: [M+H]=650.0.

Example 501-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(230)

From coupling of 40 and 6. Column chromatography with EtOAc:hexanes(1:1) gave fore fractions, then 230. Found: [M+H]=658.9.

Example 511-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(231)

From coupling of 120 and 37. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave fore fractions, followed 231. Found: [M+H]=663.0.

Example 521-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(232)

From coupling of 43 and 6. Column chromatography with EtOAc:hexanes(1:1) gave fore fractions, then 232. Found: [M+H]=605.7.

Example 531-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)butan-2-ol(233)

From coupling of 46 and 6. Column chromatography with EtOAc:hexanes(1:4) gave fore fractions, then 233 Found: [M+H]=619.7.

Example 541-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol(234)

From coupling of 30 and 37. Column chromatography with EtOAc:hexanes(1:4) gave fore fractions, then 234. Found: [M+H]=633.7.

Example 552-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol(235)

From coupling of 30 and 29. Column chromatography with EtOAc:hexanes(1:4) gave fore fractions, then 235. Found: [M+H]=629.6.

Example 562-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol(236)

From coupling of 22 and 29. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave fore fractions, followed 236. Found: [M+H]=656.0.

Example 571-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol(237)

From coupling of 30 and 6. Column chromatography with EtOAc:hexanes(1:1) gave fore fractions, then 237. Found: [M+H]=598.0.

Example 581-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol(238)

From coupling of 22 and 37. Column chromatography with EtOAc:hexanes(1:1), then EtOAc gave 238. Found: [M+H]=659.9.

Example 591-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(6-(diethylamino)pyridin-3-yl)-4-(dimethylamino)butan-2-ol(239)

From coupling of 50 and 4. Column chromatography of the crude productusing mixtures of hexane/ethyl acetate gave 239. Found: [M+H]=666.1.

Example 601-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-2-methoxypyridin-4-yl)butan-2-ol(240)

From coupling of 55 and 6. Column chromatography with 9:1 hexane/EtOAceluted unreacted starting material XX, then chromatography with 1:2hexane/EtOAc gave 240. Found: [M+H]=614.9.

Example 611-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol(241)

From coupling of 120 and 63. Column chromatography with 1:1 DCM/EtOAc,followed by EtOAc eluted 241. Found: [M+H]=656.6.

Example 621-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-4-methoxyphenyl)butan-2-ol(242)

From coupling of 66 and 6. Column chromatography with 9:1 hexane/EtOAceluted unreacted starting material, then elution with 1:1 hexane/EtOAceluted 242. Found: [M+H]=613.7.

Example 631-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol(243)

From coupling of 72 and 6. Column chromatography with 2:1 hexane/EtOAceluted unreacted starting material, then chromatography with 1:1hexane/EtOAc gave 243. Found: [M+H]=656.7.

Example 641-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-(ethylthio)pyridin-4-yl)butan-2-ol(244)

From coupling of 76 and 6. Column chromatography of the crude product,eluting with 10-50% EtOAc/hexane afforded 244 Found: [M+H]=669.7.

Example 651-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(245)

From coupling of 80 and 6. Column chromatography with 1:1 hexane/EtOAceluted unreacted starting material, then chromatography with 1:3hexane/EtOAc, then 19:1 EtOAc/MeOH eluted 245. Found: [M+H]=627.0.

Example 661-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6-trimethoxypyridin-3-yl)butan-2-ol(246)

From coupling of 86 and 6. Column chromatography with 2:1 hexane/EtOAceluted unreacted starting material, then chromatography with 1:1hexane/EtOAc gave 246. Found: [M+H]=656.7.

Example 671-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)butan-2-ol(247)

From coupling of 90 and 6. Column chromatography of the crude producteluting with DCM to remove unreacted starting material followed bymixtures of hexane/EtOAc in increasing eluent strength gave 247. Found:[M+H]=639.7.

Example 681-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)butan-2-ol(248)

From coupling of 120 and 93. Repeated flash chromatography of the crudeproduct eluting with DCM to remove unreacted starting material followedby mixtures of hexane/EtOAc in increasing eluent strength gave 248.Found: [M+H]=639.7.

Example 691-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)butan-2-ol(249)

From coupling of 96 and 6. Repeated flash chromatography of the crudeproduct using mixtures of hexane/EtOAc in increasing eluent strengthgave 249. Found: [M+H]=653.7.

Example 701-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-isopropoxy-2-methoxypyridin-3-yl)butan-2-ol(250)

From coupling of 100 and 6. Column chromatography of the crude productusing 0-5% MeOH/DCM gave 250. Found: [M+H]=654.7.

Example 711-(6-Bromo-2-methoxyquinolin-3-yl)-1-(4-chloro-2-methoxythiazol-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol(251)

From coupling of 107 and 6. Column chromatography with 9:1 hexane/EtOAceluted unreacted starting material, then chromatography with 4:1hexane/EtOAc followed by 2:1 hexane/EtOAc eluted 251. Found:[M+H]=636.6.

Example 723-(1-(2,5-Dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(252)

General Cyanation Procedure

A solution of 245 (0.61 g, 0.969 mmol) in DMF (6 mL, anhydrous) waspurged with nitrogen and heated to 55° C. for 10 min.Tri(o-tolyl)phosphine (0.044 g, 0.145 mmol), zinc dust (0.006 g, 0.097mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.067 g, 0.073 mmol)were then added, and the reaction was again purged with nitrogen andheated for another 10 min at 55° C. Zinc cyanide (0.063 g, 0.533 mmol)was then added and the reaction mixture was heated to 65° C. for 4hours. The reaction was diluted with water and extracted with EtOActhree times. The organic layer was washed with brine three times, driedand evaporated. Column chromatography with 1:1 hexane/EtOAc followed by1:3 hexane/EtOAc afforded 252 (0.41 g, 74%) as a foamy solid. Found:[M+H]=573.8.

The following compounds were synthesised using the General CyanationProcedure. Each coupled product was resolved into its four opticalisomers using preparative chiral HPLC.

Example 733-(2-(Benzofuran-2-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(253)

By cyanation of 186 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-6%MeOH:DCM gave 253. Found: [M+H]=510.1.

Example 743-(2-(Benzofuran-7-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(254) F

By cyanation of 188 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-6%MeOH:DCM gave 254. Found: [M+H]=510.2.

Example 753-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carbonitrile(255)

By cyanation of 191 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-6%MeOH:DCM gave 255. Found: [M+H]=533.2.

Example 763-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile(256)

By cyanation of 199 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-6%MeOH:DCM gave 256. Found: [M+H]=602.2.

Example 773-(2-(Benzofuran-7-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile(257)

By cyanation of 201 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-6%MeOH:DCM gave 257. Found: [M+H]=581.0.

Example 783-(2-(2,6-Dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carbonitrile(258)

By cyanation of 111 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-10%MeOH:DCM gave 258. Found: M+H]=518.7.

Example 793-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(259)

By cyanation of 211 using the General Cyanation Procedure. The crudeproduct was purified by column chromatography. Elution with 0-5%MeOH:DCM gave 259. Found: [M+H]=615.8.

Example 803-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(260)

By cyanation of 219 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1) gave fore fractions, then 260.Found: [M+H]=531.2.

Example 813-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(261)

By cyanation of 221 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1), then EtOAc gave 261. Found:[M+H]=571.0.

Example 823-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(262)

By cyanation of 229 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:2), then EtOAc gave fore fractions,followed by 262. Found: [M+H]=597.1.

Example 833-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(263)

By cyanation of 231 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:2), then EtOAc gave fore fractions,followed by 263. Found: [M+H]=610.2.

Example 843-(2-(2,6-Diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(264)

By cyanation of 223 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1) gave fore fractions, then 264.Found: [M+H]=599.2.

Example 853-(1-(2,3-Dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(265)

By cyanation of 232 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1) gave fore fractions, then 265.Found: [M+H]=552.9.

Example 863-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(266)

By cyanation of 237 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1) gave fore fractions, then 266.Found: [M+H]=545.1.

Example 873-(4-(Dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile(267)

By cyanation of 228 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:3) gave fore fractions, then 267.Found: [M+H]=576.8.

Example 883-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(268)

By cyanation of 234 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (2:1) gave fore fractions, then 268.Found: [M+H]=580.8.

Example 893-(2-(2,6-Bis(methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(269)

By cyanation of 235 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (2:1) gave fore fractions, then 269.Found: [M+H]=576.7.

Example 903-(2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(270)

By cyanation of 236 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1), then EtOAc gave 270. Found:[M+H]=602.7.

Example 913-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(271)

By cyanation of 238 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (2:1), then EtOAc gave fore fractions,followed by 271. Found: [M+H]=606.8.

Example 923-(2-(2,6-Diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(272)

By cyanation of 227 using the General Cyanation Procedure. Columnchromatography with EtOAc:hexanes (1:1) gave fore fractions, then 272.Found: [M+H]=573.1.

Example 933-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile(273)

By cyanation of 109 using the General Cyanation Procedure. Columnchromatography with EtOAc, then EtOAc:MeOH (4:1) gave 273. Found:[M+H]=557.0.

Example 943-(1-(2,3-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(274)

By cyanation of 248 using the General Cyanation Procedure except thatthe reaction mixture was heated at 45° C. overnight. Flashchromatography of the crude product using mixtures of hexanes/EtOAc inincreasing eluent strength afforded 274 as a bright yellow foam. Found:[M+H]=586.8.

Example 953-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile(275)

By cyanation of 249 using the General Cyanation Procedure except thatthe reaction mixture was heated at 55° C. overnight. Columnchromatography of the crude product using mixtures of hexanes/EtOAc inincreasing eluent strength gave 275. Found: [M+H]=600.8.

Example 963-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carbonitrile(276)

By cyanation of 250 using the General Cyanation Procedure except thatthe reaction mixture was heated at 60° C. for 2 hours. Columnchromatography of the crude product using mixtures of hexanes/EtOAc inincreasing eluent strength gave 276. Found: [M+H]=601.8.

Example 973-(2-(2,6-Dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile(277)

By cyanation of 102 using the General Cyanation Procedure except thatthe reaction mixture was heated at 40° C. overnight. Columnchromatography of the crude product using mixtures of hexanes/EtOAc inincreasing eluent strength and finally 5% MeOH in EtOAc gave 277. Found:[M+H]=516.8.

Example 983-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trimethoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carbonitrile(278)

By cyanation of 246 using the General Cyanation Procedure. Columnchromatography of the crude product using a mixture of 1:1 hexanes/EtOAcgave 278. Found: [M+H]=603.8.

Example 99 Activity Against Replicating M. tuberculosis H₃₇Rv

Representative compounds were evaluated for Minimum InhibitoryConcentration (MIC) versus M. tuberculosis H₃₇Rv (ATCC 27294) using themicroplate Alamar Blue assay (MABA) using 7H12 media (Collins, L., andS. G. Franzblau. 1997. Microplate alamar blue assay versus BACTEC 460system for high-throughput screening of compounds against Mycobacteriumtuberculosis and Mycobacterium avium. Antimicrob Agents Chemother41:1004-9.).

Cultures were incubated in 200 ml medium in 96-well plates for 7 days at37° C. Alamar Blue and Tween 80 were added and incubation continued for24 hours at 37° C. Fluorescence was determined at excitation/emissionwavelengths of 530/590 nm, respectively. The MIC was defined as thelowest concentration effecting a reduction in fluorescence of 90%relative to controls.

MIC data for representative compounds of the invention are provided inTable 1:

TABLE 1 M. tuberculosis Example MIC (μg/ml) cLogP MWt 1 <0.02 6.3 580.512 0.07 6.64 545.47 3 0.47 5.59 584.48 4 0.02 5.55 580.51 5 0.02 6.86642.56 7 0.03 5.61 606.51 9 <0.02 4.77 627.53 10 0.03 5.61 606.51 11<0.02 5.94 586.54 12 <0.01 7.41 634.56 13 <0.02 5.8 614.5 14 0.06 6.64545.47 15 0.02 7.11 561.53 16 <0.02 6.64 642.56 17 <0.01 6.33 628.53 18<0.01 5.61 655.58 19 <0.01 6.36 655.58 20 <0.02 5.3 641.56 21 <0.02 7.19634.56 22 <0.02 6.89 620.54 23 <0.02 6.13 669.61 24 <0.02 6.88 669.61 250.01 7.13 608.57 26 0.01 6.58 655.58 27 0.01 6.71 598.1 28 0.01 5.83655.58 29 <0.004 6.36 606.51 30 <0.004 5.68 667.6 31 <0.01 6.88 669.6132 0.02 7.2 564.11 33 <0.02 6.39 600.57 34 0.04 7.35 608.57 35 <0.026.11 654.59 36 <0.02 5.83 655.58 37 0.08 4.83 594.54 38 <0.02 4.72 597.539 <0.02 5.94 584.48 40 0.07 7.09 545.51 41 0.02 5.72 624.52 42 <0.026.06 613.49 43 0.07 6.78 652.58 44 <0.02 7.5 674.69 45 <0.02 6.4 646.6346 <0.02 5.43 659.65 47 <0.02 7.49 626.56 48 <0.02 6.14 630.57 49 0.046.24 650.48 50 <0.01 6.18 659.66 51 <0.004 5.21 663.51 52 0.01 6.81606.55 53 <0.004 7.37 620.58 54 0.01 6.88 634.48 55 <0.004 7.1 630.63 560.01 7.4 684.71 57 <0.01 6.44 598.5 58 <0.01 6.17 660.5 59 <0.02 7.13666.65 60 <0.02 5.10 615.49 61 0.02 4.80 657.55 62 0.01 5.80 614.5 630.01 5.15 657.55 64 0.01 6.68 670.66 65 <0.02 5.12 627.53 66 <0.01 5.15657.55 67 0.01 5.83 640.57 68 0.01 5.08 640.57 69 <0.004 6.36 654.59 70<0.004 5.96 655.58 71 0.03 5.68 637.97 72 <0.01 3.76 573.64 73 0.08 5.42509.57 74 0.04 5.42 509.57 75 0.19 4.59 532.65 76 <0.02 5 601.69 77<0.02 5.84 580.67 78 0.09 4.01 518.63 79 0.01 5.53 615.72 80 0.03 4.58530.39 81 0.02 4.36 570.64 82 <0.02 4.89 596.6 83 <0.02 3.86 609.62 840.03 5.42 598.69 85 0.02 5.45 552.66 86 <0.02 5.08 544.63 87 0.02 4.79576.68 88 0.01 5.53 580.6 89 0.02 5.74 576.75 90 0.01 5.02 602.77 910.02 4.81 606.62 92 <0.02 6.14 572.67 93 0.01 3.78 556.62 94 0.06 3.73586.68 95 0.03 5.01 600.71 96 <0.004 4.6 601.7 97 0.01 4 516.57 98 <0.013.79 603.67The invention is further described in the following numbered paragraphs:

1. A compound of formula (I):

including any stereochemically isomeric form thereof,wherein:

-   R₁ is -phenyl, optionally mono- or bi-substituted independently with    lower alkyl, halogen or alkoxy,    -   5- or 6-membered heteroaryl, optionally mono-, bi- or        tri-substituted independently with lower alkyl, halogen, alkoxy,        —SCH₃, SCH₂CH₃, —N(CH₂CH₃)₂ or —N(CH₃)₂,    -   benzofuranyl,    -   2,3-dihydrobenzo[b][1,4]dioxin-5-yl,    -   2,3-dihydro-1H-inden-4-yl or    -   5,6,7,8-tetrahydro naphthalene-1-yl;-   R₂ and R₃, independently of each other, are hydrogen or lower alkyl;-   R₄ is -phenyl, optionally mono- or bi-substituted independently with    halogen or lower alkyl,    -   5- or 6-membered heteroaryl, optionally mono-, bi- or        tri-substituted independently with alkoxy, —O-cycloalkyl,        —S-loweralkyl, difluoromethoxy or —N(CH₃)₂,    -   benzofuranyl,    -   benzo[b]thiophenyl or    -   2,3-dihydro-1H-indenyl; and-   R₅ is halogen or cyano,-   or a pharmaceutically acceptable salt thereof.

2. The compound according to paragraph 1, wherein R₁ is unsubstitutedphenyl.

3. The compound according to paragraph 1, wherein R₁ is phenyl mono- orbi-substituted independently with lower alkyl, halogen or alkoxy.

4. The compound according to paragraph 1, wherein R₁ is an unsubstituted5- or 6-membered heteroaryl.

5. The compound according to paragraph 1, wherein R₁ is pyridinyl.

6. The compound according to paragraph 1, wherein R₁ is a 5- or6-membered heteroaryl mono-, bi- or tri-substituted independently withlower alkyl, halogen, alkoxy, —SCH₃, —SCH₂CH₃, —N(CH₂CH₃)₂ or —N—(CH₃)₂.

7. The compound according to paragraph 1, wherein R₁ pyridinyl mono-,bi- or tri-substituted independently with lower alkyl, halogen, alkoxy,—SCH₃, —SCH₂CH₃, —N(CH₂CH₃)₂ or —N—(CH₃)₂.

8. The compound according to paragraph 1, wherein R₁ is pyridinyl mono-or bi-substituted independently with lower alkyl, halogen, alkoxy,—SCH₃, —SCH₂CH₃, —N(CH₂CH₃)₂ or —N—(CH₃)₂.

9. The compound according to paragraph 1, wherein R₁ is benzofuranyl,2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or5,6,7,8-tetrahydro naphthalene-1-yl.

10. The compound according to paragraph 1, wherein R₂ and R₃,independently of each other, are hydrogen or methyl.

11. The compound according to paragraph 1, wherein both R₂ and R₃ aremethyl.

12. The compound according to paragraph 1, wherein R₄ is unsubstitutedphenyl.

13. The compound according to paragraph 1, wherein R₄ is phenyl mono- orbi-substituted independently with halogen or lower alkyl.

14. The compound according to paragraph 1, wherein R₄ is anunsubstituted 5- or 6-membered heteroaryl.

15. The compound according to paragraph 1, wherein R₄ is pyridinyl.

16. The compound according to paragraph 1, wherein R₄ is a 5- or6-membered heteroaryl mono-, bi- or tri-substituted independently withalkoxy, —O-cycloalkyl, —S-loweralkyl, difluoromethoxy or —N(CH₃)₂.

17. The compound according to paragraph 1, wherein R₄ is pyridinylmono-, bi- or tri-substituted independently with alkoxy, —O-cycloalkyl,—S-loweralkyl, difluoromethoxy or —N(CH₃)₂.

18. The compound according to paragraph 1, wherein R₄ is pyridinyl mono-or bi-substituted independently with alkoxy, —O-cycloalkyl,—S-loweralkyl, difluoromethoxy or —N(CH₃)₂.

19. The compound according to paragraph 1, wherein R₄ is benzofuranyl,benzo[b]thiophenyl or 2,3-dihydro-1H-indenyl.

20. The compound according to paragraph 1, wherein R₅ is halogen.

21. The compound according to paragraph 1, wherein R₅ is bromine,chlorine or iodine.

22. The compound according to paragraph 1, wherein R₅ is bromine.

23. The compound according to paragraph 1, wherein R₅ is cyano.

24. The compound according to paragraph 1, wherein said compound is:

-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol;-   2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(m-tolyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   2-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol;-   2-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   2-(Benzofuran-5-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(5-methylthiophen-2-yl)butan-2-ol;-   2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   2-(Benzofuran-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;-   2-(Benzo[b]thiophen-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)butan-2-ol;-   2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;-   2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)-1-(m-tolyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-methoxy-6-propoxypyridin-4-yl)butan-2-ol;-   1-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-methoxy-6-propoxypyridin-4-yl)butan-2-ol;-   1-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol;-   1-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2,5-dimethylthiophen-3-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol;-   1-(6-Bromno-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromno-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-methoxypyridin-3-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(3-fluorophenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinolin-3-yl)-1-phenylbutan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol;-   2-(2,6-Bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethyl    amino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;-   1-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;-   2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;-   2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(6-(diethyl    amino)pyridin-3-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(3-fluoro-2-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(3-fluoro-4-methoxyphenyl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-(dimethylamino)-6-(ethylthio)pyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6-trimethoxypyridin-3-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethyl    amino)-1-(5-isopropoxy-2-methoxypyridin-3-yl)butan-2-ol;-   1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(4-chloro-2-methoxythiazol-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;-   3-(1-(2,5-Dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(Benzofuran-2-yl)-4-(dimethyl    amino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(Benzofuran-7-yl)-4-(dimethyl    amino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(Benzofuran-7-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(1-(2,3-Dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(4-(Dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Bis(methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(1-(2,3-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carbonitrile;-   3-(2-(2,6-Dimethoxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile;    or-   3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trimethoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carbonitrile.

25. A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to paragraph 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to paragraph 24, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A method for the treatment of tuberculosis, comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to paragraph 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

28. A method for the treatment of tuberculosis, comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to paragraph 24, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

The invention claimed is:
 1. A compound of formula (I):

including any stereochemically isomeric form thereof, wherein: R₁ isphenyl, optionally mono- or bi-substituted independently with loweralkyl, halogen or alkoxy, 5- or 6-membered heteroaryl, optionally mono-,bi- or tri-substituted independently with lower alkyl, halogen, alkoxy,—SCH₃, —SCH₂CH₃, —N(CH₂CH₃)₂ or —N(CH₃)₂, benzofurany, 2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or 5,6,7,8-tetrahydronaphthalene-1-yl; R₂ and R_(3,) independently of each other, arehydrogen or lower alkyl; R₄ is 5- or 6-membered heteroaryl mono-, bi- ortri-substituted independently with alkoxy, —O-cycloalky, —S-loweralkyl,difluoromethoxy or —N(CH₃)₂, benzofuranyl, benzo[b]thiophenyl or2,3-dihydro-1H-indenyl; and R₅ is halogen or cyano, or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1, wherein R₁ is unsubstituted phenyl.
 3. The compound accordingto claim 1, wherein R₁ is phenyl mono- or bi-substituted independentlywith lower alkyl, halogen or alkoxy.
 4. The compound according to claim1, wherein R₁ is an unsubstituted 5- or 6-membered heteroaryl.
 5. Thecompound according to claim 1, wherein R₁ pyridinyl.
 6. The compoundaccording to claim 1, wherein R₁ is a 5- or 6-membered heteroaryl mono-,bi- or tri-substituted independently with lower alkyl, halogen, alkoxy,—SCH₃, —SCH₂CH₃, —N(CH₂CH₃ )₂ or —N—(CH₃)₂.
 7. The compound according toclaim 1, wherein R₁ pyridinyl mono-, bi- or tri-substitutedindependently with lower alkyl, halogen, alkoxy, —SCH₃, —SCH₂CH₃,—N(CH₂CH₃)₂ or —N—(CH₃)₂.
 8. The compound according to claim 1, whereinR₁ pyridinyl mono- or bi-substituted independently with lower alkyl,halogen, alkoxy, —SCH₃, —SCH₂CH₃, —N(CH₂CH₃)₂ or —N—(CH₃)₂.
 9. Thecompound according to claim 1, wherein R₁ is benzofuranyl,2,3-dihydrobenzo[b][1,4]dioxin-5-yl, 2,3-dihydro-1H-inden-4-yl or5,6,7,8-tetrahydro naphthalene-1-yl.
 10. The compound according to claim1, wherein R₂ and R₃, independently of each other, are hydrogen ormethyl.
 11. The compound according to claim 1, wherein both R₂ and R₃are methyl.
 12. The compound according to claim 1, wherein R₄ is a 5- or6-membered heteroaryl mono-, bi- or tri-substituted independently withalkoxy, —O-cycloalkyl, —S-loweralkyl, difluoromethoxy or —N(CH₃)₂. 13.The compound according to claim 1, wherein R₄ is pyridinyl mono-, bi- ortri-substituted independently with alkoxy, —O-cycloalkyl, —S-loweralkyldifluoromethoxy or —N(CH₃)₂.
 14. The compound according to claim 1,wherein R₄ is pyridinyl mono- or bi-substituted independently withalkoxy, —O-cycloalkyl, —S-loweralkyl, difluoromethoxy or —N(CH₃)₂. 15.The compound according to claim 1, wherein R₄ is benzofuranyl,benzo[b]thiophenyl or 2,3-dihydro-1H-indenyl.
 16. The compound accordingto claim 1, wherein R₅ is halogen.
 17. The compound according to claim1, wherein R₅ is bromine, chlorine or iodine.
 18. The compound accordingto claim 1, wherein R₅ is bromine.
 19. The compound according to claim1, wherein R₅ is cyano.
 20. A compound, wherein said compound is:1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimetboxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol;2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(5,6-dimethoxypyridin-3-yl)-4-(dimethylamino)-2-(3-fluorophenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(m-tolyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl) butan-2-ol; 2-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol;2-(Benzofuran-2-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;2-(Benzofuran-5-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-methylthiophen-2-yl)butan-2-ol;2-(Benzofuran-7-yl)-1-(6-bromo-2-metboxyquinolin-3-yl)-1-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;2-(Benzofuran-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;2-(Benzo[b]thiophen-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-pbenylbutan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-methoxypyridin-4-yl)butan-2-ol;2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-isopropoxy-6-methoxypyridin-4-yl)butan-2-ol;2-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-ethoxy-6-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxymidin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(2-isopropoxy-6-methoxypyridin-4-yl)-1-(m-tolyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxy-6-propoxypyridin-4-yl)butan-2-ol;1-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)4-(dimethylamino)-2-2-methoxy-6-propoxypyridin-4-yl)butan-2-ol;1-(Benzofuran-7-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-cyclobutoxy-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)butan-2-ol;1-(6-Chloro-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5-dimethylthiophen-3-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(m-tolyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-methoxypyridin-3-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,3-dihydro-1H-inden-4-yl)-4-(dimethylamino)-1-phenylbutan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(6-iodo-2-methoxyquinolin-3-yl)-1-phenylbutan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol;2-(2,6-Bis(ethylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)butan-2-ol;1-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(6-bromo-2-methoxyquinolin-3-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2-(difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-diethoxypyridin-4-yl)-1-(6-(diethylamino)pyridin-3-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)1-(3-fluoro-2-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluoro-4-methoxyphenyl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,3,6-trimethoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-(ethylthio)pyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,5-dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2,5,6-trimethoxypyridin-3-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-2-(dimethylamino)-6-methoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yI)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(5-isopropoxy-2-methoxypyridin-3-yl)butan-2-ol;1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(4-chloro-2-methoxythiazol-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)butan-2-ol;3-(1-(2,5-Dimethoxypyridin-3-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(Benzofuran-2-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(Benzofuran-7-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(Beznofuran-7-yl)-4-(dimethylamino)-2-hydroxy-1-(2-isopropoxy-6-methoxypyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)-1-(5-methylthiophen-2-yl)butyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-ethoxy-6-isopropoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(3-fluorophenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Diethoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(1-(2,3-Dihydro-1H-inden-4-yl)-2-(2,6-dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(4-(Dimethylamino)-1-(2-fluoro-3-methoxyphenyl)-2-hydroxy-2-(2-methoxy-6-(methylthio)pyridin-4-yl)butyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Bis(methylthio)pyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Bis(methylthio)pyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2-(Difluoromethoxy)-6-methoxypyridin-4-yl)-1-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)-4-(dimethylamino)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Diethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-fluoro-3-methylphenyl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(1-(2,3-Dihydrobenzo[b][1,4]dioxin-5-yl)-2-(2,6-dimethoxypyridin-4-yl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile;3-(1-(2,3-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-(2-(dimethylamino)-6-methoxypyridin-4yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-1-(2-(dimethylamino)-6-ethoxypyridin-4-yl)-2-hydroxybutyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(5-isopropoxy-2-methoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carbonitrile;3-(2-(2,6-Dimetboxypyridin-4-yl)-1-(3-fluorophenyl)-2-hydroxy-4-(methylamino)butyl)-2-methoxyquinoline-6-carbonitrile;or3-(2-(2,6-Dimethoxypyridin-4-yl)-4-(dimethylamino)-2-hydroxy-1-(2,5,6-trimethoxypyridin-3-yl)butyl)-2-methoxyquinoline-6-carbonitrile,or any stereochemically isomeric form thereof, or a pharmaceuticallyacceptable salt thereof.
 21. A pharmaceutical composition, comprising atherapeutically effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 22. A pharmaceutical composition, comprising atherapeutically effective amount of a compound according to claim 20, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 23. A method for the treatment of tuberculosis,comprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 1, ora pharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 24. A method for the treatment of tuberculosis,comprising the step of administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 20, ora pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.